Benzamide-containing compounds and their use in the treatment of pain

ABSTRACT

The present invention is directed to benzamide-containing compounds of formula I 
                         
or pharmaceutically acceptable salts thereof which inhibit the P2X7 receptor, and their use in the treatment of pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.14/050,431, filed Oct. 10, 2013, which claims benefit of U.S.Provisional Application No. 61/713,113, filed Oct. 12, 2012. Each ofthese applications is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to novel compounds which inhibit theP2X₇ receptor. Separate aspects of the invention are directed topharmaceutical compositions comprising said compounds and uses of thecompounds to treat pain, inflammation, neurological disorders, orneuropsychiatric disorders.

BACKGROUND ART

The purinergic 2X₇ (P2X₇) receptor is a ligand-gated ion channel whichis activated by extracellular ATP and is present on a variety of celltypes, including microglia in the central nervous system and other cellsinvolved in inflammation and immune system function. The P2X₇ receptorhas been shown to have a role in cytolysis in the immune system(Surprenant, et al. Science, 272, 735-41, 1996), and is involved inactivation of lymphocytes and monocyte/macrophages leading to theincreased release of pro-inflammatory cytokines (e.g., TNFα and IL1β)from these cells (Ferrari, et al. Neuropharmacol, 36, 1295-301, 1997).

Studies have shown that inhibiting P2X₇ receptor activation insituations of inflammation (e.g., rheumatoid arthritis and otherautoimmune diseases, osteoarthritis, asthma, chronic obstructivepulmonary disease and inflammatory bowel disease) or interstitialfibrosis results in a therapeutic effect (DiVirgilio, et al. Drug DevRes, 45, 207-13, 1998). These and other studies indicate that P2X₇receptor antagonists may find use in the treatment and prophylaxis ofpain, including acute, chronic and neuropathic pain (Chessel, et al,Pain, 114, 386-96, 2005).

Inhibiting P2X₇ activation may also diminish or reduce cell death causedby prolongation of activated P2X₇ receptors, indicating a potentialtherapeutic intervention for said antagonists in nervous system injuryor degeneration (Sperlagh, et al., Progress in Neurobiology, 7, 327-346,2006). Vianna, et al. (Epilepsia, 43, 27-229, 2002) also revealed apotential role for P2X₇ receptors in the pathogenesis of epilepsy.Interestingly, because of the P2X₇ receptor's role in microgliaactivation and proliferation in the central nervous system (CNS), aself-propagating cycle of neuroinflammation and neurodegenerationresults from P2X₇ receptor activation in areas of the brain (Monif, etal, J Neurosci, 29, 3781-91, 2009).

Thus, P2X₇ receptor antagonists, particularly small molecules withsufficient brain-penetrable properties, are desirable as useful agentsfor therapeutic intervention in the central nervous system for treatingpain, inflammation, neurological and neurodegenerative disorders,neuropsychiatric disorders, or other disorders for which the reductionor otherwise stabilization of pro-inflammatory cytokines is beneficial.The present invention fulfills this need, and provides further relatedadvantages.

SUMMARY OF THE INVENTION

An objective of the present invention is to provide compounds thatinhibit P2X₇ receptors. Accordingly, the present invention relates tocompounds of Formula I.

-   -   wherein R¹ is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl        or 5 membered heteroaryl, each of which is optionally        substituted with one or more C₁₋₆alkyl, halogen, hydroxy,        C₁₋₆hydroxyalkyl, C₁₋₄fluoroalkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,        C₁₋₄fluoroalkoxy, cyano or —SO₂R⁸;    -   wherein R² is C₃₋₆cycloalkyl, C₃₋₆cyclohetalkyl,        C₁₋₄fluoroalkyl, C₁₋₄fluoroalkoxy, C₁₋₄alkoxy, C₁₋₆alkenyl,        C₁₋₆alkynyl, 6 membered heteroaryl, phenyl or C₁₋₄alkyl        optionally substituted with one or more R⁹;    -   wherein R³ is hydrogen, fluorine, C₁₋₄alkyl or C₁₋₄fluoroalkyl;        or    -   wherein R² and R³ combine with the carbon to which they are        attached to form cyclohexyl, tetrahydropyranyl, piperazinyl,        piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl,        homomorpholinyl, homopiperidinyl or homopiperazinyl each of        which is optionally substituted with one or more C₁₋₆alkyl,        C₁₋₆alkenyl, C₃₋₆-cycloalkyl, C₁₋₆alkoxy, oxo, —NR⁶R⁷ or        fluorine;    -   wherein R⁴ is halogen, C₁₋₄fluoroalkyl, cyano, cyclopropyl,        C₁₋₄alkyloxy, C₁₋₄fluoroalkyloxy, —SO₂R⁸, —NR⁶R⁷ or C₁₋₆alkyl;    -   wherein R⁵ is halogen, C₁₋₆alkyl, C₁₋₄fluoroalkyl, cyano,        —SO₂R⁸, —NR⁶R⁷, C₁₋₆alkoxy, C₁₋₄fluoroalkoxy or C₃₋₆-cycloalkyl;    -   wherein R⁶ and R⁷ independently of each other are hydrogen or        C₁₋₆alkyl;    -   wherein R⁸ is C₁₋₆alkyl, C₃₋₆cycloalkyl or C₁₋₄fluoroalkyl;    -   wherein R⁹ is C₁₋₆alkyl, C₃₋₆cycloalkyl, —NR¹⁰R¹¹,        C₁₋₄fluoroalkyl or 3 to 7 membered heterocyclyl which is        optionally substituted with one or more C₁₋₆alkyl, halogen,        hydroxy, C₁₋₄fluoroalkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,        C₁₋₄fluoroalkoxy or cyano;    -   wherein R¹⁰ and R¹¹ independently of each other are hydrogen or        C₁₋₆alkyl; or    -   wherein R¹⁰ and R¹¹ combine with the nitrogen to which they are        attached to form piperazinyl, piperidinyl, morpholinyl,        pyrrolidinyl, azetidinyl, homomorpholinyl, homopiperidinyl or        homopiperazinyl each of which is optionally substituted with one        or more C₁₋₄alkyl, C₁₋₆alkoxy, oxo or fluorine; and    -   wherein n is 0-3; or a pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising acompound of the invention or a pharmaceutically acceptable salt thereof,and optionally a pharmaceutically acceptable carrier, excipient ordiluent.

The compounds of Formula I may contain one or more stereogenic orasymmetric centers, such as one or more asymmetric carbon atoms. Thecompounds of Formula I may thus be present as mixtures of stereoisomersor preferably as pure stereoisomers. Mixtures of stereoisomers can beseparated in a manner known to a person skilled in the art.

The present invention further provides methods for treating pain orinflammation in a subject, comprising administering to a subjectsuffering from pain or inflammation a therapeutically effective amountof a compound of Formula I.

The present invention further provides methods for treating an affectivedisorder in a subject comprising administering to a subject sufferingfrom an affective disorder a therapeutically effective amount of atleast one compound of Formula I.

The present invention further provides methods for treating aneurological disorder or neurodegenerative disorder in a subjectcomprising administering to a subject suffering from a neurologicaldisorder or neurodegenerative disorder a therapeutically effectiveamount of at least one compound of Formula I.

The present invention further provides methods for treating depression,major depressive disorder, treatment resistant depression, anxiety,obsessive-compulsive disorder, post-traumatic stress disorder (PTSD),neuropathic pain, osteoarthritis, rheumatoid arthritis, psoriaticarthritis, inflammatory bowel disease, multiple sclerosis, epilepsy,Parkinson's Disease, Huntington's Disease and Alzheimer's disease, whichinvolves administering a compound of Formula I.

The present invention also provides the use a compound of Formula I forthe manufacture of a medicament for the treatment of affectivedisorders.

The present invention also provides a compound of Formula I for use intreating an affective disorder in a subject.

These and other aspects of the invention will become apparent uponreference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

As previously indicated, the present invention is based on the discoveryof the compounds of Formula I, which are inhibitors of the P2X₇receptor, and as such, are useful for the treatment of relateddisorders. Additionally, certain aspects of the invention are explainedin greater detail below but this description is not intended to be adetailed catalog of all the different ways in which the invention may beimplemented, or all the features that may be added to the instantinvention. Hence, the following specification is intended to illustratesome embodiments of the invention, and not to exhaustively specify allpermutations, combinations and variations thereof.

-   In one embodiment, R¹ is optionally substituted phenyl.-   In one embodiment, R¹ is optionally substituted pyridyl.-   In another embodiment, R¹ is optionally substituted pyrazinyl.-   In one embodiment, R¹ is optionally substituted pyrimidyl.-   In one embodiment, R¹ is optionally substituted 5 membered    heteroaryl.-   In one embodiment, R² and R³ combine with the nitrogen to which they    are attached to form optionally substituted piperazinyl.-   In yet embodiment, R² and R³ combine with the nitrogen to which they    are attached to form optionally substituted piperidinyl.-   In one embodiment, R² and R³ combine with the nitrogen to which they    are attached to form optionally substituted morpholinyl.-   In one embodiment, R² and R³ combine with the nitrogen to which they    are attached to form optionally substituted pyrrolidinyl.-   In one embodiment, R² and R³ combine with the nitrogen to which they    are attached to form optionally substituted pyrrolo.-   In one embodiment, R² and R³ combine with the nitrogen to which they    are attached to form optionally substituted imidazo.-   In one embodiment, R² and R³ combine with the nitrogen to which they    are attached to form optionally substituted homomorpholinyl-   In one embodiment, R² and R³ combine with the nitrogen to which they    are attached to form optionally substituted homopiperidinyl-   In one embodiment, R² and R³ combine with the nitrogen to which they    are attached to form optionally substituted homopiperazinyl-   In one embodiment, R² and R³ combine with the nitrogen to which they    are attached to form optionally substituted azetidinyl.-   In one embodiment, R⁴ is chlorine, methyl or trifluoromethyl.-   In one embodiment, n is 0.-   In one embodiment, n is 1.-   In one embodiment, n is 2.

As used herein, the term “C₁-C₆ alkyl” refers to a straight chained orbranched saturated hydrocarbon having from one to six carbon atomsinclusive. Examples of such substituents include, but are not limitedto, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl,2-methyl-2-propyl, 2-methyl-1-propyl, n-pentyl and n-hexyl. Similarly,the term “straight chained or branched C₁-C₃ alkyl” refers to asaturated hydrocarbon having from one to three carbon atoms inclusive.Examples of such substituents include, but are not limited to, methyl,ethyl and n-propyl.

Likewise, the term “C₁-C₆ alkoxy” refers to a straight chained orbranched saturated alkoxy group having from one to six carbon atomsinclusive with the open valency on the oxygen.

Examples of such substituents include, but are not limited to, methoxy,ethoxy, n-butoxy, t-butoxy and n-hexyloxy.

As used herein, the term “C₁-C₄ fluoroalkyl” refers to a straightchained or branched saturated hydrocarbon having from one to four carbonatoms inclusive substituted with one or more fluorine atoms. Examples ofsuch substituents include, but are not limited to, trifluoromethyl,pentafluoroethyl, 1-fluoroethyl, monofluoromethyl, difluoromethyl and1,2-difluoroethyl.

Likewise, the term “C₁₋₆ hydroxyalkyl” refers to a straight chained orbranched saturated hydrocarbon group substituted with one hydroxylgroup. Examples of such substituents include, but are not limited to,hydroxymethyl, 1-hydroxy-1-methyl-ethyl and 1-hydroxyethyl.

Likewise, the term “C₁₋₆ alkenyl” refers to a straight chained orbranched hydrocarbon containing 1-6 carbon atoms and having one or moredouble bonds. Examples of such substituents include, but are not limitedto, allyl, butenyl and 2-hexenyl.

Likewise, the term “C₁₋₆ alkynyl” refers to a straight chained orbranched hydrocarbon containing 1-6 carbon atoms and having one or moretriple bonds. Examples of such substituents include, but are not limitedto, ethynyl, propargyl and 3-hexynyl.

Likewise, the term “C₁-C₄ fluoroalkoxy” refers to a straight chained orbranched saturated alkoxy group having from one to four carbon atomsinclusive with the open valency on the oxygen and in which one or morecarbon atoms are substituted with one or more fluorine atoms. Examplesof such substituents include, but are not limited to, monofluoromethoxy,1,1-difluoroethoxy and 1-monofluoro-n-butoxy.

Likewise the term “C₃₋₆ cycloalkyl” refers to saturated monocyclichydrocarbon groups. Examples of such systems include, but are notlimited to, cyclopropyl, cyclobutyl or cyclohexyl

Likewise the term “5 membered heteroaryl” refers to a fully unsaturatedaromatic monocyclic ring system having 1-4 heteroatoms. Examples of suchsystems include, but are not limited to, thienyl, furyl, imidazolyl andpyrrolyl.

Likewise the term “6 membered heteroaryl” refers to a fully unsaturatedaromatic monocyclic ring system having 1-3 heteroatoms. Examples of suchsystems include, but are not limited to, pyridinyl, pyrimidinyl,pyrazinyl and pyridazinyl.

Likewise the term “3 to 7 membered heterocycle” refers to fullysaturated monocyclic ring system having 1-3 heteroatoms. Examples ofsuch systems include, but are not limited to, tetrahydropyranyl,piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl,homomorpholinyl, homopiperidinyl and homopiperazinyl

The term “halogen” refers to fluorine, chlorine, bromine and iodine.

As used herein, the phrase “effective amount” when applied to a compoundof the invention, is intended to denote an amount sufficient to cause anintended biological effect. The phrase “therapeutically effectiveamount” when applied to a compound of the invention is intended todenote an amount of the compound that is sufficient to ameliorate,palliate, stabilize, reverse, slow or delay the progression of adisorder or disease state, or of a symptom of the disorder or disease.In an embodiment, the method of the present invention provides foradministration of combinations of compounds. In such instances, the“effective amount” is the amount of the combination sufficient to causethe intended biological effect.

The term “treatment” or “treating” as used herein means ameliorating orreversing the progress or severity of a disease or disorder, orameliorating or reversing one or more symptoms or side effects of suchdisease or disorder. “Treatment” or “treating”, as used herein, alsomeans to inhibit or block, as in retard, arrest, restrain, impede orobstruct, the progress of a system, condition or state of a disease ordisorder. For purposes of this invention, “treatment” or “treating”further means an approach for obtaining beneficial or desired clinicalresults, where “beneficial or desired clinical results” include, withoutlimitation, alleviation of a symptom, diminishment of the extent of adisorder or disease, stabilized (i.e., not worsening) disease ordisorder state, delay or slowing of a disease or disorder state,amelioration or palliation of a disease or disorder state, and remissionof a disease or disorder, whether partial or total, detectable orundetectable.

Pharmaceutically Acceptable Salts

The present invention also comprises salts of the present compounds,typically, pharmaceutically acceptable salts. Such salts includepharmaceutically acceptable acid addition salts. Acid addition saltsinclude salts of inorganic acids as well as organic acids.

Representative examples of suitable inorganic acids includehydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic,nitric acids and the like. Representative examples of suitable organicacids include formic, acetic, trichloroacetic, trifluoroacetic,propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic,lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic,picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic,tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic,gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids,theophylline acetic acids, as well as the 8-halotheophyllines (forexample, 8-bromotheophylline and the like). Further examples ofpharmaceutically acceptable inorganic or organic acid addition saltsinclude the pharmaceutically acceptable salts listed in S. M. Berge, etal., J. Pharm. Sci., 1977, 66, 2.

Furthermore, the compounds of this invention may exist in unsolvated aswell as in solvated forms with pharmaceutically acceptable solvents suchas water, ethanol and the like.

Racemic forms may be resolved into the optical antipodes by knownmethods, for example, by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Separation of such diastereomericsalts can be achieved, e.g. by fractional crystallization. The opticallyactive acids suitable for this purpose may include, but are not limitedto d- or l-tartaric, mandelic or camphorsulfonic acids. Another methodfor resolving racemates into the optical antipodes is based uponchromatography on an optically active matrix. The compounds of thepresent invention may also be resolved by the formation andchromatographic separation of diastereomeric derivatives from chiralderivatizing reagents, such as, chiral alkylating or acylating reagents,followed by cleavage of the chiral auxiliary. Any of the above methodsmay be applied either to resolve the optical antipodes of the compoundsof the invention per se or to resolve the optical antipodes of syntheticintermediates, which can then be converted by methods described hereininto the optically resolved final products which are the compounds ofthe invention.

Additional methods for the resolution of optical isomers, known to thoseskilled in the art, may be used. Such methods include those discussed byJ. Jaques, A. Collet and S. Wilen in Enantiomers, Racemates, andResolutions, John Wiley and Sons, New York, 1981. Optically activecompounds can also be prepared from optically active starting materials.

Pharmaceutical Compositions

The present invention further provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula Iand a pharmaceutically acceptable carrier. The present invention alsoprovides a pharmaceutical composition comprising a therapeuticallyeffective amount of one of the specific compounds disclosed in theExperimental Section and a pharmaceutically acceptable carrier.

The compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers or excipients, ineither single or multiple doses. The pharmaceutical compositionsaccording to the invention may be formulated with pharmaceuticallyacceptable carriers or diluents as well as any other known adjuvants andexcipients in accordance with conventional techniques such as thosedisclosed in Remington: The Science and Practice of Pharmacy, 19^(th)Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

The pharmaceutical compositions may be specifically formulated foradministration by an oral route. Pharmaceutical compositions for oraladministration include solid dosage forms such as capsules, tablets,dragees, pills, lozenges, powders and granules. Where appropriate, thecompositions may be prepared with coatings such as enteric coatings orthey may be formulated so as to provide controlled release of the activeingredient such as sustained or prolonged release according to methodswell known in the art. Liquid dosage forms for oral administrationinclude solutions, emulsions, suspensions, syrups and elixirs.

The term “inhibit” or “inhibiting” as used herein means to reduce,diminish, block or even eliminate, such as in e.g. “inhibiting P2X₇receptor activity”. “Inhibiting P2X₇ receptor activity” or “inhibitingP2X₇ activity” as used herein means, e.g. reducing or even eliminatingthe ability of a P2X₇ receptor to exhibit a cellular response, such asinhibiting the response to stimuli or agonist ligands, or inhibiting theproduction or accumulation of IL1β.

The present invention also provides a method of treating a disease ordisorder, the method comprising administering a therapeuticallyeffective amount of at least one compound of the present invention or apharmaceutically acceptable salt thereof to a mammal suffering from (orat risk for) the disease or disorder, or otherwise in need of thetreatment. The present invention also provides a method of treating painor inflammation, the method comprising administering a therapeuticallyeffective amount of at least one compound of the present invention or apharmaceutically acceptable salt thereof to a mammal in need thereof. Inan embodiment, the pain that may be treated using the compoundsdescribed herein, including acute, chronic or inflammatory pain, iscaused by neuropathic pain, post-operative pain, morphine tolerance,fibromyalgia, neuralgias, headache, osteoarthritis, rheumatoidarthritis, psoriatic arthritis, irritable bowel syndrome or inflammatorybowel disease.

In other embodiments, the disease or disorder that may be treated usingthe compounds described herein is a neurological disorder orneurodegenerative disorder, such as epilepsy, multiple sclerosis,Parkinson's disease, Huntington's disease or Alzheimer's disease. Asused herein, the term “neurological disorder” means a disorder of thenervous system, and includes, but is not limited to, the disorders asdescribed hereinabove. Based on the well-known meaning of disorders ofthe nervous system, neurological disorders result from structural,biochemical, electrical, or cellular (neuronal or microglial) signalingabnormalities that may occur in the brain or spinal cord of theafflicted mammal. As used herein, the term “neurodegenerative disorder”means a disorder characterized by symmetrical and progressive loss ofstructure or function of neurons, such as death of neurons or reducedgrowth of neurons. Such loss of neurons may affect motor, sensory, orcognitive neuronal systems. As such, treating a neurological orneurodegenerative disorder using the compounds described herein mayresult in the amelioration or relief of symptoms of the neurological orneurodegenerative disorder, such symptoms as paralysis, muscle weakness,poor coordination, uncontrolled movements, seizures, confusion, alteredlevels of consciousness, memory loss, emotional instability, loss ofsensation, pain, and similar symptoms.

In an embodiment, the disease or disorder is a neuropsychiatricdisorder, such as an affective disorder. As used herein, “affectivedisorder” means a mental disorder characterized by a consistent,pervasive alteration of mood, and affecting thoughts, emotions andbehaviors. Affective disorders include mood disorders as described inDSM-IV-TR® (American Psychiatric Association, 2000, Diagnostic andStatistical Manual of Mental Disorders (4th ed., text rev.)doi:10.1176/appi.books.9780890423349; which is incorporated by referenceherein). As such, treating an affective disorder using the compoundsdescribed herein may result in the amelioration, stabilization orotherwise diminishment or relief of symptoms of the affective disorder,such symptoms as mood instability, manic episodes, feelings of guilt orworthlessness, sleep disturbances, agitation, or the like. Examples ofaffective disorders include, but are not limited to, depressivedisorders, anxiety disorders, bipolar disorders, dysthymia andschizoaffective disorders. Anxiety disorders include, but are notlimited to, generalized anxiety disorder, panic disorder,obsessive-compulsive disorder, phobias, and post-traumatic stressdisorder (PTSD). Depressive disorders include, but are not limited to,major depressive disorder (MDD), catatonic depression, melancholicdepression, atypical depression, psychotic depression, postpartumdepression, treatment-resistant depression, bipolar depression,including bipolar I and bipolar II, and mild, moderate or severedepression. Personality disorders include, but are not limited to,paranoia, antisocial and borderline personality disorders.

In an embodiment of the invention, the affective disorder treated usingthe compounds described herein is depression, major depressive disorder(MDD), treatment-resistant depression, bipolar disorder, generalizedanxiety disorder, panic disorder, obsessive-compulsive disorder, orpost-traumatic stress disorder (PTSD), or a combination thereof.

The present invention provides a method of treating an affectivedisorder in a subject, comprising administering to a subject in need ofsuch treatment a therapeutically effective amount of at least onecompound of Formula I.

The present invention provides a method of inhibiting P2X₇ activity in asubject, comprising administering to a subject in need thereof atherapeutically effective amount of at least one compound of Formula I.

The present invention also provides a method of inhibiting production oraccumulation of IL1β, comprising administering to a subject in need ofsuch treatment a therapeutically effective amount of at least onecompound of Formula I.

In an embodiment, the present invention provides the use of a compoundof Formula I for the manufacture of a medicament for the treatment ofaffective disorders. The present invention also provides the use of acompound of Formula I for the manufacture of a medicament for theinhibition of P2X₇ activity. The present invention further provides theuse of a compound of Formula I for the manufacture of a medicament forthe inhibition of production or accumulation of IL1β.

In an embodiment, the present invention provides at least one compoundof Formula I for use in treating an affective disorder in a subject. Inan embodiment, the present invention provides at least one compound ofFormula I for use in inhibiting P2X7 activity in a subject. In anembodiment, the present invention provides at least one compound ofFormula I for use in inhibiting production or accumulation of IL1β in asubject.

The invention also provides a compound of Formula I for use in therapyof a subject, for example, in the treatment of affective disorders.

EXPERIMENTAL SECTION

The compounds of the present invention of the general formula I, whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and n are as defined abovecan be prepared by the methods outlined in the following reaction scheme1 and in the examples. In the described methods, it is possible to makeuse of variants or modifications, which are themselves known to chemistsskilled in the art or could be apparent to the person of ordinary skillin this art. Furthermore, other methods for preparing compounds of theinvention will be readily apparent to the person skilled in the art inlight of the following reaction schemes and examples.

The schemes may involve the use of selective protecting groups duringthe synthesis of the compounds of the invention. One skilled in the artwould be able to select the appropriate protecting group for aparticular reaction. It may be necessary to incorporate protection andde-protection strategies for substituents such as amino, amido,carboxylic acid and hydroxyl groups in the synthetic methods describedbelow to synthesize the compounds of Formula I. Methods for protectionand de-protection of such groups are well known in the art, and may befound in T. Green, et al., Protective Groups in Organic Synthesis, 1991,2^(nd) Edition, John Wiley & Sons, New York.

General Methods

Analytical LC-MS data were obtained using one of the methods identifiedbelow.

Method A: Performed using electrospray ionization (ESI) operating inpositive mode via a Waters ZQ (Waters Corp.) mass spectrometer (all fromWaters Corp., Milford, Mass., USA), an Agilent 1100 LC pump (AgilentTechnologies, Inc., Santa Clara, Calif.), and Agilent 1100 autosampler,with a 200 μl/min split to the ESI source with inline Agilent 1100 diodearray detector (DAD) and variable wavelength detector (VWD) at 254 nm,and an 800 uL/min split to a Waters evaporative light scatteringdetector (ELSD). Separation was performed on a Inertsil ODS-3 3 μm50×4.6 mm column using a mobile phase of A) Water 1% Acetonitrile and0.2% Ammonium formate; and B) acetonitrile, which was delivered in agradient fashion over 1.70 minutes going from 20% B to 85% B. Thenstepped to 100% B at 1.85 minutes and maintained at 100% B until 1.99minutes.

Method B: Performed using electrospray ionization (ESI) operating inpositive mode via a Waters ZQ (Waters Corp.) mass spectrometer (all fromWaters Corp., Milford, Mass., USA), an Agilent 1100 LC pump (AgilentTechnologies, Inc., Santa Clara, Calif.), and Agilent 1100 autosampler,with a 200 μl/min split to the ESI source with inline Agilent 1100 diodearray detector (DAD) and variable wavelength detector (VWD) at 254 nm,and an 800 uL/min split to a Waters evaporative light scatteringdetector (ELSD). Separation was performed on a Inertsil C₈ 3 μm 50×4.6mm column using a mobile phase of A) Water 1% Acetonitrile and 0.2%Ammonium formate; and B) acetonitrile, which was delivered in a gradientfashion over 1.70 minutes going from 30% B to 90% B. Then stepped to100% B at 1.85 minutes and maintained at 100% B until 1.99 minutes.

Method C: A PE Sciex API 150EX instrument equipped with atmosphericpressure photo ionisation and a Shimadzu LC-8A/SLC-10A LC system wasused. Column: 3.0×30 mm Waters Symmetry C18 column with 2.2 μm particlesize; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.965:0.035) andB=acetonitrile/trifluoroacetic acid (99.965:0.035); Method: Lineargradient elution with A:B=90:10 to 20:80 in 1.5 minutes and with a flowrate of 1.2 mL/minutes.

Method D: A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEHC18 1.7 μm; 2.1×50 mm; Column temperature: 60° C.; Solvent system:A=water/trifluoroacetic acid (99.965:0.035) andB=acetonitrile/water/trifluoroacetic acid (94.965:5:0.035); Method:Linear gradient elution with A:B=90:10 to 0:100 in 1.0 minutes and witha flow rate of 1.2 mL/minutes.

Method E: A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEHC18 1.7 μm; 2.1×50 mm; Column temperature: 60° C.; Solvent system:A=water/formic acid (99.9:0.1) and B=acetonitrile/water/formic acid(94.9:5:0.1); Method: Linear gradient elution with A:B=90:10 to 0:100 in1.0 minutes and with a flow rate of 1.2 mL/minutes.

Method F: An Agilent 1200 LCMS system with ELS detector was used.Column: Agilent TC-C18 5 μm; 2.1×50 mm; Column temperature: 50° C.;Solvent system: A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=99:1 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/minutes.

Method G: An Agilent 1200 LCMS system with ELS detector was used.Column: Agilent TC-C18 5 μm; 2.1×50 mm; Column temperature: 50° C.;Solvent system: A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=90:10 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/minutes.

Preparative LC-MS-purification was performed on a PE Sciex API 150EXinstrument with atmospheric pressure chemical ionization. Column: 50×20mm YMC ODS-A with 5 m particle size; Solvent system:A=water/trifluoroacetic acid (99.965:0.035) andB=acetonitrile/water/trifluoroacetic acid (94.965:5:0.035); Method:Linear gradient elution with A:B=80:20 to 0:100 in 7 minutes and with aflow rate of 22.7 mL/minute. Fraction collection was performed bysplit-flow MS detection.

Preparative SFC was performed on a Thar 80 instrument. Exemplifiedconditions can be, but not limited to: Column AD 250×30 mm with 20 μmparticle size; Column temperature: 38° C., Mobile phase: SupercriticalCO₂/EtOH (0.2% NH₃H₂O)=45/55.

¹H NMR spectra were recorded at 300, 400, 500 or 600 MHz on BrukerAvance instruments. TMS was used as internal reference standard.Chemical shift values are expressed in ppm. The following abbreviationsare used for multiplicity of NMR signals: s=singlet, d=doublet,t=triplet, q=quartet, qui=quintet, h=heptet, dd=double doublet,dt=double triplet, dq=double quartet, tt=triplet of triplets,m=multiplet, br s=broad singlet and br=broad signal.

Benzoic acids of formula II are commercially available or available bymethods described in the literature (see for example Shaikh, TanveerMahammad Ali, J. Org. Chem (2006), 71, 5043-5046 and Mongin, Florence;Tetrahedron Lett. (1996), 37, 6551-6554).

Abbreviations are in accordance with to the ACS Style Guide: “The ACSStyle guide—A manual for authors and editors” Janet S. Dodd, Ed. 1997,ISBN: 0841234620

Preparation of Intermediates1-Bromomethyl-1-trifluoromethyl-cyclopropane

Step 1: To a solution of compound1-trifluoromethyl-cyclopropanecarboxylic acid (2 g, 13 mmol) in dry THF(80 mL) was added LAH (592 mg, 16 mmol) in portions at 0° C. and theresulting mixture was heated at 40° C. overnight. H₂O (592 mg, 16 mmol)was added to quench the reaction at 0° C. and followed by 2N NaOH (0.6mL). After filtration, the filtrate was distilled to remove the mostsolvent to give crude (1-trifluoromethyl-cyclopropyl)-methanol (1.2 gcrude), which was used in the next step without further purification.

To a solution of (1-trifluoromethyl-cyclopropyl)-methanol (1.2 g, 8.57mmol) and Et₃N (1.04 g, 10.28 mmol) in dry DMF (10 mL) at −10° C. wasadded methanesulfonyl chloride (981 mg, 8.57 mmol) over 20 minutes,while retaining the inner temperature at 0° C. After the addition wascomplete, the resulting solution was stirred at 0° C. for 30 minutes,the resulting mixture was filtered and washed with DMF (3 mL). To thecombined filtrates was added sodium bromide (3.7 g, 36 mmol) and theresulting mixture was stirred at room temperature overnight. The mixturewas cooled in ice, followed by addition of pentane (20 mL) and water (15mL) while retaining the mixture at 0° C., prior to liquid separation.The organic phase was dried over Na₂SO₄ and filtered. The filtrate wasdistilled to remove the most of pentane to give1-bromomethyl-1-trifluoromethyl-cyclopropane (0.9 g crude), which wasused without further purification.

1-Bromomethyl-1-difluoromethyl-cyclopropane

Step 1: A suspension of cyano-acetic acid ethyl ester (11.3 g, 0.1 mol),1,2-Dibromo-ethane, NH₄(n-Bu)₄Br and K₂CO₃ in DMF (100 mL) was heated to80° C. overnight. The mixture was poured into water (600 mL) andextracted with EtOAc (3×50 mL). The combined organic layer was washedwith brine, dried over Na₂SO₄, concentrated under reduced pressure togive the crude product, which was purified by column chromatography onsilica gel (petroleum ether:EtOAc=10:1-5:1) to give1-cyano-cyclopropanecarboxylic acid ethyl ester (10 g, yield: 72%). ¹HNMR (CDCl₃ 400 MHz): δ4.21 (q, J=7.2 Hz, 2H), 1.65-1.61 (m, 2H),1.58-1.55 (m, 2H), 1.28 (t, J=7.2 Hz, 3H).

Step 2: To concentrated sulfuric acid (102 mL) was added1-cyano-cyclopropanecarboxylic acid ethyl ester (60 g, 0.43 mol)dropwise followed by 2-methylpentan-2,4-diol (52 g, 0.44 mmol) dropwiseat 0° C. The mixture was stirred for an additional 1 h at 0° C. thenpoured onto ice-water. The aqueous phase was washed with AcOEt (3×200mL) and then basified to pH 12 with 10 M NaOH. The resulting mixture wasextracted with EtOAc (3×500 mL). The combined organic layer was washedwith brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby column chromatography on silica gel to give1-(4,4,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl)-cyclopropanecarboxylicacid ethyl ester (65 g, yield: 63.2%). ¹H NMR (CDCl₃ 400 MHz):δ4.21-4.06 (m, 3H), 1.73-1.69 (m, 1H), 1.40-1.10 (m, 17H).

Step 3: NaBH₄ (3.18 g, 13.3 mmol) was dissolved in H₂O (10 mL) and adrop of 10 M NaOH was added. To a solution of1-(4,4,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl)-cyclopropanecarboxylicacid ethyl ester (10 g, 0.04 mol) in THF (33 mL) and ethanol (33 mL) wasadded the above alkaline solution of NaBH₄ dropwise at −40° C. followedby 12M HCl (about 0.1 mL, the pH of the reaction mixture was adjusted to6˜8). The resulting mixture was stirred at −40° C. for 1.5 hour. Thereaction mixture was poured into water (100 mL) and basified with 10MNaOH to pH=10. The mixture was extracted with EtOAc (3×100 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄ andconcentrated to give crude1-(4,4,6-trimethyl-[1,3]oxazinan-2-yl)-cyclopropanecarboxylic acid ethylester (9.0 g), which was used in the next step without purification.

Step 4: Oxalic acid (11.2 g, 0.124 mol) was dissolved in water (40 mL)and 1-(4,4,6-trimethyl-[1,3]oxazinan-2-yl)-cyclopropanecarboxylic acidethyl ester (15 g, 0.062 mol) was added. Steam distillation of thismixture was carried out until 500 mL of distillate had been collected.The distillate was saturated with NaCl and extracted with EtOAc (2×100mL). The organic extracts were dried over Na₂SO₄ and concentrated underreduced pressure to give 1-formyl-cyclopropanecarboxylic acid ethylester (4.5 g, 51%). ¹H NMR (CDCl₃ 400 MHz): δ10.39 (s, 1H), 4.26(q,J=7.2 Hz, 2H), 1.67-1.64 (m, 2H), 1.61-1.58 (m, 2H), 1.31 (t, J=7.2 Hz,3H).

Step 5: To a solution of 1-formyl-cyclopropanecarboxylic acid ethylester (4.0 g, 28.1 mmol) in DCM (40 mL) was added DAST (18.6 mL, 0.14mol) at 0° C. dropwise and the resulting mixture was stirred at roomtemperature overnight. NaHCO₃ solution (10 mL) was added to quench thereaction and extracted with DCM (100×3 mL). The organic extracts weredried over Na₂SO₄ and concentrated under reduced pressure to give1-difluoromethyl-cyclopropanecarboxylic acid ethyl ester (3 g, 65%). ¹HNMR (CDCl₃400 MHz): δ6.42 (t, J=57.2 Hz, 1H), 4.18(q, J=7.2 Hz, 2H),1.28-1.21 (m, 7H).

1-Bromomethyl-1-difluoromethyl-cyclopropane was prepared as describedabove for the synthesis of 1-Bromomethyl-1-trifluoromethyl-cyclopropanestarting from 1-difluoromethyl-cyclopropanecarboxylic acid ethyl ester

3-Acetyl-3-chlorodihydrofuran-2(3H)-one

SO₂Cl₂ (68 g, 0.504 mol) was added to 3-acetyldihydrofuran-2(3H)-one (64g, 0.499 mol) dropwise at room temperature under stirring for a periodof 1˜1.5 h. Then the mixture was stirred at room temperature for 2 h.The resulting mixture was diluted with water, stirred for 30 minutes,the organic layer was separated and dried over MgSO₄, filtered anddistilled with oil pump at 80° C. to give3-acetyl-3-chlorodihydrofuran-2(3H)-one as colorless oil (54 g, 66.8%yield). ¹H NMR (CDCl₃ 400 MHz): δ4.45-4.36 (m, 2H), 3.19-3.15 (m, 1H),2.54 (s, 3H), 2.53-2.44 (m, 1H).

3-Acetyl-3-fluorodihydrofuran-2(3H)-one

Et₃N-3HF (112.2 g, 0.66 mol) and Et₃N (66.7 g, 0.66 mol) was added tosolution of 3-acetyl-3-chlorodihydrofuran-2(3H)-one (54 g, 0.33 mol) inCH₃CN (165 mL). The mixture was heated to 80° C. for 3 h under stirring.Subsequently, approximately 140 mL of CH₃CN are distilled off, and theresidue was poured into water. The mixture was extracted with DCM,washed with aq.NaHCO₃, dried over MgSO₄, concentrated to give the crudeproduct, which was purified by distillation with oil pump at 70° C. togive 3-acetyl-3-fluorodihydrofuran-2(3H)-one as colorless oil (28.8 g,yield: 60%). ¹H NMR (CDCl₃ 400 MHz): δ4.48-4.40 (m, 2H), 2.83-2.57 (m,1H), 2.55-2.41 (m, 4H).

1-(1-Fluorocyclopropyl)ethanone

3-acetyl-3-fluorodihydrofuran-2(3H)-one (26 g, 0.178 mol) was added tothe solution of KI (12 g, 0.07 mol) in NMP (50 ml) dropwise at 190° C.under a pressure of 0.5 bar. By distilling off continuously, 8 g ofcrude product was obtained and the crude product was purified bydistillation again at 100° C. under a pressure of 0.5 bar to give1-(1-fluorocyclopropyl)ethanone as light yellow oil (3.3 g, yield: 18%).¹H NMR (CDCl₃ 400 MHz): δ2.40 (s, 3H), 1.38-1.33 (m, 4H).

1-Fluorocyclopropanecarboxylic acid

Bromine (14.8 g, 93 mmol) was added slowly to NaOH (12.36 g, 300 mmol)in water (50 mL) below 10° C. Afterwards,1-(1-fluorocyclopropyl)ethanone (3.3 g, 30 mmol) was added slowly below0° C. and the reaction mixture was then stirred for one hour at roomtemperature. Na₂S₂O₅ was added until a colorless solution was formed. 50mL of AcOEt was added. The aqueous phase was separated and acidified topH 2 with aq. HCl (2M) and extracted with AcOEt (3×50 mL). This organicphase was dried over Na₂SO₄ and concentrated to give1-fluorocyclopropanecarboxylic acid as a white solid (2.2 g, 66% yield).¹H NMR (CDCl₃ 400 MHz): δ1.49-1.45 (m, 4H).

1-Bromomethyl-1-fluoromethyl-cyclopropane was prepared as describedabove for the synthesis of 1-Bromomethyl-1-trifluoromethyl-cyclopropanestarting from 1-fluorocyclopropanecarboxylic acid.

(6-Trifluoromethyl-pyridin-3-yl)-acetonitrile

Step 1: (6-Trifluoromethyl-pyridin-3-yl)-methanol BH₃.THF (1 M solutionin THF, 393 mL, 393 mmol) was added to a solution of6-trifluoromethyl-nicotinic acid (25.0 g, 131 mmol) in dry THF (300 mL)at 0° C. under nitrogen with vigorous stirring. The mixture wasgradually warmed to room temperature and stirred for 16 hours. Themixture was concentrated under reduced pressure and the residue was thendissolved in DCM and cooled to 0° C. Methanol was carefully added untilgas evolution ceased and the solution was concentrated again underreduced pressure. The residue was purified by silica gel chromatography(5% methanol in DCM). The fractions containing product were collectedand concentrated under reduced pressure. The residue was dissolved inDCM, washed with saturated aqueous sodium bicarbonate, brine, dried oversodium sulfate, filtered and concentrated under reduced pressure toafford (6-trifluoromethylpyridin-3-yl)-methanol as a yellow oil (19.7 g,85%). 1H NMR (400 MHz, CDCl₃) δ ppm 8.63 (s, 1 H), 7.91 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz 1H), 4.80 (s, 2 H), 3.84 (br. s., 1 H). 19F NMR(400 MHz, CDCl₃):168 cm-1. MS m/z 178.12

Step 2: 5-Chloromethyl-2-trifluoromethylpyridine

Thionyl chloride (40.3 mL, 554 mmol) was slowly added to a solution of(6-trifluoromethylpyridin-3-yl)-methanol (19.6 g, 111 mmol) in DCM (195mL) at room temperature under nitrogen. The reaction mixture was stirredat reflux for 16 hours then concentrated under reduced pressure. Theresidue was dissolved in AcOEt (200 mL), washed with saturated aqueoussodium bicarbonate, brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to give crude5-chloromethyl-2-trifluoromethylpyridine as a brown oil which was usedin the following step without further purification (19.5 g, 90%). ¹H NMR(400 MHz, CDCl₃) δ ppm 8.74 (s, 1 H), 7.94 (d, J=8.4 Hz, 1 H), 7.72 (d,J=8.4 Hz 1H), 4.66 (s, 2 H). 19F NMR (400 MHz, CDCl₃) :168 cm-1. MS m/z196.15; 198.09

Step 3: (6-Trifluoromethylpyridin-3-yl)-acetonitrile

5-Chloromethyl-2-trifluoromethylpyridine (19.5 g, 99.7 mmol) in ethanol(160 mL) was added to a solution of potassium cyanide (9.74 g, 150 mmol)in water (80 mL) at 90° C. over 30 minutes. The mixture was stirred at90° C. for 3 hours. Most of the ethanol was removed under reducedpressure and the aqueous layer was extracted with AcOEt (3×100 mL). Thecombined organic extracts were washed with water, brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (30% AcOEt in hexanes)to afford (6-trifluoromethylpyridin-3-yl)-acetonitrile as a brown oil(9.79 g, 75%). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.63 (s, 1 H), 7.90 (d,J=8.0 Hz, 1 H), 7.70 (d, J=8.0 Hz 1 H), 3.88 (s, 2 H). 19F NMR(400 MHz,CDCl₃):168 cm-1. MS m/z 187.14

(2-Methyl-pyrimidin-5-yl)-methanol

Step 1: A three-neck 2-L round bottomed flask with an immersionthermometer and an addition funnel was charged with DMF (400 mL) andcooled to 0° C. POCl₃ (178 g, 1.16 mol) was carefully added to thereaction via an addition funnel maintaining an internal temperature of5-10° C. After 2 h, the yellow solution was treated with bromoaceticacid (50 g, 0.36 mol) and heated to 90° C. overnight. The mixture wascooled and a short-path distillation head was attached. DMF wasdistilled from the red-orange oil at 120° C. under high vacuum. Thetarry residue was cooled to room temperature and treated with ice (about10 g). Aqueous NaBF₄ (80 g in 160 mL H₂O) was added at 0° C. As thesolid residue slowly dissolved, a vigorous exotherm occurred. Theyellow-orange precipitate that formed at 0° C. was collected byfiltration and re-dissolved in hot CH₃CN (2 L). After hot-filtration,excess NaBF₄ was removed and the filtrate was cooled to −30° C. Thecrystalline precipitate was collected and dried in vacuum to give theintermediate salt (60 g, yield: 47%).

Step 2: To 500 mL of EtOH was added sodium (12 g, 0.50 mol) in portionsat room temperature and the resulting mixture was stirred until thesodium was dissolved completely. To a suspension of the previouslyprepared salt (60 g, 0.17 mol) and acetamidine hydrochloride (17.4 g,0.19 mol) in EtOH (2.5 L) was added the above solution at roomtemperature and the resulting mixture was heated to reflux for 5 h.After filtration, the solvent was removed under reduced pressure to givethe remains, which was suspended in H₂O (200 mL) and extracted with DCM(3 mL×100). The organic layer was washed with brine, dried over Na₂SO₄and concentrated. The crude product was purified by columnchromatography on silica gel (petroleum ether:EtOAc=5:1 to 2:1) toafford 2-methyl-pyrimidine-5-carbaldehyde (10 g, yield: 50%). ¹H NMR(CDCl₃ 400 MHz): δ10.10 (s, 1H), 9.07 (s, 2H), 2.84 (s, 3H).

A solution of 2-methyl-pyrimidine-5-carbaldehyde (5 g, 41 mmol) in MeOH(100 mL) was added NaBH₄ (2.3 g, 61.5 mmol) at 0° C. in portions and theresulting mixture was stirred at room temperature for 1 h. The solventwas removed under reduced pressure to give the remains, which wassuspended in H₂O (20 mL) and extracted with EtOAc (5×50 ml). The organiclayer was dried over Na₂SO₄ and concentrated to afford the titlecompound (2 g, yield: 39%). ¹H NMR (CDCl₃ 400 MHz): δ8.64 (s, 2H), 4.72(s, 2H), 2.73 (s, 3H).

(2-Methyl-pyrimidin-5-yl)-acetonitrile was prepared as described abovefor the synthesis of (6-trifluoromethyl-pyridin-3-yl)-acetonitrilestarting from (2-methyl-pyrimidin-5-yl)-methanol

(5-Chloro-pyridin-3-yl)-acetonitrile

Step 1: 5-Chloro-nicotinic acid methyl ester

To a solution of 5-chloro-nicotinic acid (20.0 g, 127 mmol, purchasedfrom Matrix Scientific, Columbia, S.C., USA) in methanol (200 mL) at 0°C. was added thionyl chloride (18.6 mL, 255 mmol). The reaction mixturewas refluxed for 4 hours. After cooling to room temperature the mixturewas diluted with saturated aqueous sodium bicarbonate, extracted withAcOEt (3×300 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure to afford crude 5-chloro-nicotinic acid methylester (17.2 g, 79%). ¹H NMR (400 MHz, CDCl₃) δ ppm 9.10 (d, J=1.4 Hz, 1H), 8.75 (d, J=2.3 Hz, 1 H), 8.29 (d, J=2.0 Hz, 1H), 3.98 (s, 3 H). MSm/z 171.8

Step 2: (5-Chloro-pyridin-3-yl)-methanol

To a solution of 5-chloro-nicotinic acid methyl ester (17.2 g, 101 mmol)in methanol (230 mL) and DCM (230 mL) at 0° C. was added sodiumborohydride (16.4 g, 434 mmol). The reaction mixture was stirred at roomtemperature for 18 hours. After completion, the reaction mixture wasconcentrated under reduced pressure, diluted with water (300 mL) andextracted with AcOEt (3×300 mL). The combined organic layer was driedover sodium sulfate, filtered, and concentrated under reduced pressure.The residue was then purified by silica gel chromatography to afford(5-chloro-pyridin-3-yl)-methanol (7.8 g, 54%). ¹H NMR (400 MHz, DMSO-d6)δ ppm 8.45-8.52 (m, 2 H), 7.83 (s, 1 H), 5.45 (t, J=5.8 Hz, 1 H), 4.55(t, J=5.7 Hz, 2 H). MS m/z 144.1

Step 3 and 4: (5-Chloro-pyridin-3-yl)-acetonitrile

Conversion of the hydroxyl group to the chloride using thionyl chloride,followed by the displacement of the chloride by potassium cyanide wasperformed using the same procedures described for(6-trifluoromethyl-pyridin-3-yl)-acetonitrile. ¹H NMR (400 MHz, CDCl3) δppm 8.55 (d, J=2.0 Hz, 1 H), 8.50 (d, J=1.1 Hz, 1 H), 7.73 (s, 1 H),4.58 (s, 2 H). MS m/z 153.0

The following intermediates were prepared in a similar way

-   (5-Fluoro-pyridin-3-yl)-acetonitrile, from 5-fluoro-nicotinic acid;-   (2,6-Dimethyl-pyridin-3-yl)-acetonitrile, from    (2,6-dimethylpyridin-3-yl)-methanol;-   (2-Methyl-pyrimidin-5-yl)-acetonitrile, from    (2-methyl-pyrimidin-5-yl)-methanol;

3-Cyclopropyl-2-(2-trifluoromethyl-pyrimidin-5-yl)-propionitrile

Step 1: A mixture of 5-bromo-2-iodo-pyrimidine (30 g, 0.11 mol), TMSCF₃(30 g, 0.21 mol), KF (9.2 g, 0.16 mol) and CuI (30 g, 0.16 mol) in DMF(300 mL) was stirred at room temperature overnight. The reaction mixturewas quenched by NH₃.H₂O (600 mL) and extracted with EtOAc (500 mL×3).The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by column chromatography onsilica gel (Petroleum ether) to give5-bromo-2-trifluoromethyl-pyrimidine (4 g, yield: 16.7%). ¹H NMR (CDCl₃400 Hz): δ8.90 (s, 2H).

Step 2: A mixture of 5-bromo-2-trifluoromethyl-pyrimidine (1.0 g, 4.41mmol) and cyano-acetic acid ethyl ester (1.0 g, 4.41 mmol) was addedinto a suspension of t-BuOK (17.64 mL, 17.64 mmol, 1M in THF) in1,4-dioxane (10 mL) under Ar atmosphere. To the resulting mixture wasadded a solution of Pd(OAc)₂ (10 mg, 44.1 μmol) and dppf (48.9 mg, 88.2μmol) in 1,4-dioxane (1 mL). The resulting mixture was heated to 70° C.for 1 h. The reaction mixture was adjusted pH to 7˜8 with 1N AcOH andextracted with EtOAc (3×20 ml). The organic layer was dried over Na₂SO₄and concentrated. The residue was purified by column chromatography onsilica gel (EtOAc: petroleum ether=1:10) to givecyano-(2-trifluoromethyl-pyrimidin-5-yl)-acetic acid ethyl ester (140mg, yield: 12.3%). ¹H NMR (CDCl₃ 400 Hz): δ9.03 (s, 2H), 4.88 (s, 1H),4.34 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).

Step 3: A mixture of cyano-(2-trifluoromethyl-pyrimidin-5-yl)-aceticacid ethyl ester (240 mg, 0.93 mmol), bromomethyl cyclopropane (375 mg,2.78 mmol) and NaI (139 mg, 0.93 mmol) in dry dioxane (2 mL) wasdegassed and ButOK in THF (1.11 mL, 1.11 mmol) was added at roomtemperature. The resulting mixture was heated to 100-110° C. for 24 h.Saturated NH₄Cl solution was added to quench the reaction at 0° C. andextracted with EtOAc (5 mL×3). The organic layer was washed with brine,dried over Na₂SO₄ and concentrated. The crude product was purified bycolumn chromatography on silica gel (petroleum ether/EtOAc=20:1˜5:1) togive the title compound (100 mg, yield: 44.6%). ¹H NMR (CDCl₃ 400 MHz):δ8.94 (s, 2H), 4.09-4.01 (m, 1H), 2.05-1.95 (m, 1H), 1.93-1.80 (m, 1H),0.91-0.79 (m, 1H), 0.69-0.60 (m, 2H), 0.25-0.14 (m, 2H).

The following intermediates were prepared in a similar way:

-   3-(1-fluorocyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propanenitrile;-   3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propanenitrile;

4-(4-Trifluoromethyl-phenyl)-tetrahydro-pyran-4-carbonitrile

A solution of 4-trifluoromethylbenzyl cyanide (0.92 g, 5.0 mmol) andbis(2-bromoethyl)ether (2.3 mL, 18 mmol) in DMF (10 mL) at roomtemperature was treated portion wise with sodium hydride (60% in mineraloil, 0.6 g, 15 mmol) over a period of 10 mins followed by stirring atthe same temperature for 1 h. The mixture was then stirred at 70° C. for16 h. Then cooled to room temperature and the reaction mixture wasquenched with slow addition of methanol. Water (100 mL) was added andthe mixture was extracted with EtOAc (3×50 mL). The combined organicextracts were washed with water and brine and dried over sodium sulfate,filtered and concentrated. The concentrate was purified by columnchromatography using a gradient of 5% EtOAc in hexanes to 30% EtOAc inhexanes to give the title compound (1.11 g, yield: 87%). ¹H NMR (CDCl₃300 MHz): δppm 7.75 (d, 2H), 7.65 (d, 2H), 4.20-4.09 (m, 2H), 4.00-3.85(m, 2H), 2.27-2.05 (m, 4H).

The following intermediates were prepared in a similar way:

-   4-(4-Chloro-phenyl)-tetrahydro-pyran-4-carbonitrile;-   4-(6-Methylpyridin-3-yl)-tetrahydropyran-4-carbonitrile;-   4-(6-Trifluoromethylpyridin-3-yl)-tetrahydropyran-4-carbonitrile;-   4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carbonitrile;-   4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-carbonitrile;-   3-(2-methylpyrimidin-5-yl)tetrahydrofuran-3-carbonitrile;-   1-(pyridin-3-yl)cyclopentanecarbonitrile;-   1-(4-methoxyphenyl)cyclopentanecarbonitrile;-   1-methyl-4-phenylpiperidine-4-carbonitrile;-   4-(4-chlorophenyl)-1-methylpiperidine-4-carbonitrile;-   2-(4-chlorophenyl)-4-(dimethylamino)butanenitrile;-   4-(4-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-carbonitrile;

4-Methyl-2-(6-methylpyridin-3-yl)-pentanenitrile

To a cooled (0° C.) slurry of NaH (60% dispersion in oil, 2.74 g, 68.5mmol) in THF (120 mL) was added a solution of(6-methylpyridin-3-yl)-acetonitrile (8.23 g, 62.3 mmol) in THF (60 mL).The mixture was stirred at room temperature for 3 h and then warmed to40° C. for 1 h. The resulting reddish brown slurry was cooled to −20° C.and a solution of 1-bromo-2-methylpropane (8.53 g, 62.3 mmol) in THF (30mL) was added dropwise and then stirred for 18 h at room temperature.The reaction was quenched with water and extracted with AcOEt. Theorganic extracts were combined and washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (15% EtOAc in hexane) togive 7.52 g (64% yield) of4-methyl-2-(6-methylpyridin-3-yl)-pentanenitrile as an oil. ¹H NMR (400MHz, CDCl3) δ ppm 1.00 (dd, J=6.64, 4.30 Hz, 6 H), 1.53-1.70 (m, 1 H),1.71-1.99 (m, 2 H), 2.57 (s, 3 H), 3.81 (dd, J=9.57, 6.45 Hz, 1 H), 7.19(d, J=7.82 Hz, 1 H), 7.59 (dd, J=7.82, 2.34 Hz, 1 H), 8.43 (d, J=2.34Hz, 1 H).

The following intermediates were prepared in a similar way:

-   1-(4-Methoxyphenyl)-1-cyclopentanecarbonitrile;-   4-(4-Chloro-phenyl)-1-methyl-piperidine-4-carbonitrile;-   2-(4-Chloro-phenyl)-4-dimethylamino-butyronitrile;-   3-cyclopropyl-2-(pyridin-5-yl)propanenitrile;-   Cyclopropyl-(6-trifluoromethyl-pyridin-3-yl)-acetonitrile;-   3-Cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propionitrile;-   2-(5-Chloro-pyridin-3-yl)-3-cyclopropyl-propionitrile;-   2-(6-Chloropyridin-3-yl)-3-cyclopropylpropanenitrile;-   3-cyclopropyl-2-(6-fluoropyridin-5-yl)propanenitrile;-   3-Cyclopropyl-2-(2,6-dimethyl-pyridin-3-yl)-propionitrile;-   2-(2-Methyl-pyrimidin-5-yl)-3-(1-trifluoromethyl-cyclopropyl)-propionitrile;-   3-(1-Trifluoromethyl-cyclopropyl)-2-(6-trifluoromethyl-pyridin-3-yl)-propionitrile;-   3-(1-Difluoromethyl-cyclopropyl)-2-(6-trifluoromethyl-pyridin-3-yl)-propionitrile;-   2-(6-Cyclopropyl-pyridin-3-yl)-3-(1-trifluoromethyl-cyclopropyl)-propionitrile;-   2-(6-Cyclopropyl-pyridin-3-yl)-3-(1-difluoromethyl-cyclopropyl)-propionitrile;-   3-Cyclopropyl-2-(2-methyl-pyrimidin-5-yl)-propionitrile;-   2-(2-methylpyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile;-   3-(1-fluorocyclopropyl)-2-(6-(trifluoromethyl)pyridin-3-yl)propanenitrile;-   3-Cyclopropyl-2-(5-methyl-pyrazin-2-yl)-propionitrile;

5-Cyano-5-(6-fluoro-pyridin-3-yl)-2-hydroxy-cyclohex-1-enecarboxylicacid methyl ester

To a solution of (6-fluoro-pyridin-3-yl)-acetonitrile (15 g, 0.11 mol)and methyl acrylate (19 g, 0.22 mol) in dry THF (150 mL) cooled to −70°C. in dry ice-EtOH bath was added t-BuOK-THF solution (1M, 330 mL, 0.33mol) in portions. The reaction mixture was stirred at −70° C. for 4 h.After completion (LCMS) 1N HCl (aq) was added slowly at −70° C. (thetemperature of reaction mixture don't rise above −50° C.) to adjust thepH to 5-6. The THF layer was separated and the aqueous phase wasextracted with EtOAc (2×150 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to provide the crude title compound(32 g), which was used directly for the next step.

The following intermediates were prepared in a similar way:

-   5-Cyano-5-(6-trifluoromethyl-pyridin-3-yl)-2-hydroxy-cyclohex-1-enecarboxylic    acid methyl ester;-   5-Cyano-5-(6-methoxy-pyridin-3-yl)-2-hydroxy-cyclohex-1-enecarboxylic    acid methyl ester;-   5-Cyano-2-hydroxy-5-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohex-1-enecarboxylic    acid methyl ester;-   Methyl    5-cyano-2-hydroxy-5-(2-methylpyrimidin-5-yl)cyclohex-1-enecarboxylate;-   Methyl    5-cyano-2-hydroxy-5-(pyrimidin-5-yl)cyclohex-1-enecarboxylate;

1-(6-Fluoro-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile

To a solution of5-Cyano-5-(6-fluoro-pyridin-3-yl)-2-hydroxy-cyclohex-1-enecarboxylicacid methyl ester (32 g crude, 0.11 mmol) in DMSO (110 mL) was addedNaCl (7.78 g, 0.133 mol) and water (6.5 mL). The reaction mixture washeated at 160° C. for 3 h. It was cooled to room temperature and pouredinto water (300 mL). The aqueous layer was extracted with EtOAc (3×200mL). The combined organic layer was washed with brine (300 mL), driedover sodium sulphate, filtered and concentrated under reduced pressure.The residue was purified by flash column chromatography on silica gel(eluting with a gradient elution of between 10-25% EtOAc in petroleumether) to give the title compound (12 g, 50% over two steps). ¹H NMR(CDCl₃ 400 MHz): δppm 8.34 (d, J=2.4 Hz, 1H), 7.95-7.82 (m, 1H),7.00-6.92 (m, 1H), 2.95-2.87 (m, 2H), 2.60-2.2. (m, 2H), 2.50-2.40 (m,2H), 2.28-2.20 (m, 2H).

The following intermediates were prepared in a similar way:

-   1-(6-Trifluoromethyl-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile;-   1-(6-Methoxy-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile;-   4-Oxo-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexanecarbonitrile;-   4-Oxo-1-(2-methylpyrimidin-5-yl)cyclohexanecarbonitrile;-   4-Oxo-1-(pyrimidin-5-yl)cyclohexanecarbonitrile;

4,4-Difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexanecarbonitrile

To a stirred suspension of diethylamino difluorosulfiiniumtetrafluoroborate salt (23.8 g, 0.104 mol) in dry DCM (100 mL) at roomtemperature was added1-(6-fluoro-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile (12 g, 0.052mol) followed by triethylamine trihydrofluoride (25.12 g, 0.156 mol)under a nitrogen atmosphere. The reaction mixture was stirred overnightat room temperature. The resulting mixture was then quenched withsaturated aq. NaHCO₃ solution (300 mL), stirred for 10 minutes, and theresulting mixture was extracted with DCM (3×100 mL). The combinedorganic layer was washed with brine, dried over sodium sulphate,filtered and concentrated under reduced pressure to give the crudeproduct, which was purified by column chromatography on silica gel(eluting with a gradient elution of between 2-10% EtOAc in petroleumether) to afford the title compound (8 g, yield: 64%). ¹H NMR (CDCl₃ 400MHz): δppm 8.40-8.35 (m, 1H), 7.95-7.84 (m, 1H), 7.05-6.96 (m, 1H),2.40-2.10 (m, 8H).

The following intermediates were prepared in a similar way:

-   4,4-Difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexanecarbonitrile;-   4,4-Difluoro-1-(6-methoxy-pyridin-3-yl)-cyclohexanecarbonitrile;-   4,4-Difluoro-1-(2-methyl-pyrimidin-5-yl)-cyclohexanecarbonitrile;-   4,4-Difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexanecarbonitrile;-   4,4-Difluoro-1-(pyrimidin-5-yl)-cyclohexanecarbonitrile;-   4,4-difluoro-1-(5-fluoropyridin-3-yl)cyclohexanecarbonitrile;

To a solution of compound4,4-difluoro-1-(pyrimidin-5-yl)-cyclohexanecarbonitrile (1.5 g, 6.72mmol) and DFMS (6.0 g, 0.02 mol) in trifluoromethylbenzene (53 mL) andH₂O (21 mL) at room temperature was added TFA (766 mg, 6.72 mmol)followed by slow addition of t-BuOOH (5.2 g, 70% solution in H₂O) withvigorous stirring. The reaction mixture was stirred at room temperatureovernight. TLC indicates about 50% starting material remained, a secondaddition of DFMS (6.0 g, 0.02 mol) and t-BuOOH (5.2 g, 70% solution inH₂O) were added to the reaction mixture. Upon consumption of startingmaterial, the reaction mixture was portioned between DCM (20 mL) andsaturated NaHCO₃ solution (20 mL), the organic layer was separated andthe aqueous layer was extracted with DCM (3×20 ml). The organic layerwas washed with brine, dried over Na₂SO₄ and concentrated. The crudeproduct was purified by flash chromatography (Petroleum ether:EtOAc=3:1)to give1-(2-(difluoromethyl)pyrimidin-5-yl)-4,4-difluorocyclohexanecarbonitrile(800 mg, Yield: 44.4%). ¹H NMR (CDCl₃400 MHz): δ9.03 (s, 2H), 6.71 (t,J=54.4 Hz, 1H), 2.40-2.27 (m, 6H).

1-(6-Bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile

Step 1:5-(6-Chloro-pyridin-3-yl)-5-cyano-2-hydroxy-cyclohex-1-enecarboxylicacid methyl ester

To a solution of 2-(6-chloro-3-pyridinyl)acetonitrile (4.3 g, 28 mmol,purchased from Matrix Scientific, Columbia, S.C., USA) and methylacrylate (4.8 g, 56 mmol) in dry THF (150 mL) cooled to −65° C. wasadded solid potassium tert-butoxide (7.9 g, 70 mmol) under nitrogenatmosphere. The reaction mixture was stirred at −65° C. for 45 minutes.The reaction mixture was then acidified with 3 N HCl and extracted withDCM (3×150 mL). The combined organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure to give crude5-(6-chloro-pyridin-3-yl)-5-cyano-2-hydroxy-cyclohex-1-enecarboxylicacid methyl ester which was used in the next step without purification(6.0 g, 75%).

Step 2: 1-(6-Chloro-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile

To a solution of5-(6-chloro-pyridin-3-yl)-5-cyano-2-hydroxy-cyclohex-1-enecarboxylicacid methyl ester (4.2 g, 14 mmol) in DMSO (15 mL) was added sodiumchloride (0.90 g, 16 mmol) and water (0.77 mL). The reaction mixture washeated at 160° C. for 6 hours. The reaction mixture was then cooled toroom temperature and poured into water (50 mL). The aqueous layer wasextracted with diethyl ether (3×250 mL). The combined organic layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The residue obtained was purified by column chromatography onsilica gel to afford1-(6-chloro-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile (1.7 g, 52%). ¹HNMR (400 MHz, CDCl₃) δ ppm 8.59 (s, 1 H), 7.83 (dd, J=8.4, 2.2 Hz, 1 H),7.44 (d, J=8.5 Hz, 1 H), 2.89-2.98 (m, 2 H), 2.60-2.66 (m, 2 H),2.48-2.54 (m, 2 H), 2.25-2.33 (m, 2 H).

Step 3: 1-(6-Chloro-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile

To a stirred suspension of (diethylamino)difluorosulfoniumtetrafluoroborate (16.5 g, 72.1 mmol) in DCM (150 mL) at roomtemperature under nitrogen atmosphere was added1-(6-chloro-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile (4.2 g, 18 mmol)followed by triethylamine trihydrofluoride (8.68 g, 53.8 mmol). Thereaction mixture was stirred for 6 hours at room temperature. Theresulting mixture was then quenched by adding a saturated aqueoussolution of sodium bicarbonate, stirred for 10 minutes, and theresulting mixture was extracted with DCM (3×25 mL). The combined organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude residue was purified by columnchromatography on silica gel (1:10 to 1:5 AcOEt/hexanes) to afford1-(6-chloro-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (2.5 g,54%). LC-MS (m/z) 257.0 (MH+). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.56 (d,J=2.2 Hz, 1 H), 7.79 (dd, J=8.4, 2.6 Hz, 1 H), 7.42 (d, J=8.4 Hz, 1 H),2.09-2.41 (m, 8 H).

Step 4: 1-(6-Bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile

To a stirred solution of1-(6-chloro-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (1.3 g,5.1 mmol) in butyronitrile (100 mL) at room temperature under nitrogenatmosphere was added bromotrimethylsilane (1.55 g, 10.2 mmol). Thereaction mixture was heated at 120° C. for 24 hours. The reactionmixture was then cooled to room temperature and poured into water (25mL) and 10% aqueous NaOH solution (25 mL). The aqueous layer wasextracted with diethyl ether (3×250 mL). The combined organic layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The crude residue was then purified by column chromatographyon silica gel to afford1-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile as a whitesolid (1.0 g, 65%). LC-MS (m/z) 301.0 (MH+). ¹H NMR (400 MHz, CDCl₃) δppm 8.55 (d, J=2.7 Hz, 1 H), 7.69 (dd, J=8.4, 2.8 Hz, 1 H), 7.57 (d,J=8.4 Hz, 1 H), 2.09-2.41 (m, 8 H).

1-(6-Cyclopropyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile

A suspension of cyclopropylboronic acid (0.94 g, 11 mmol),1-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (1.10 g,3.67 mmol) and potassium phosphate tribasic (2.30 g, 10.8 mmol) in amixture of toluene (16 mL) and water (4 mL) at room temperature waspurged with nitrogen gas for 1 hour. Then palladium acetate (31 mg, 0.14mmol) and tricyclohexylphosphine (51 mg, 0.18 mmol) were added and themixture was heated at 110° C. for 18 hours. After cooling to roomtemperature a saturated aqueous solution of ammonium chloride was added,followed by water. The organic layer was separated and the aqueous layerwas extracted again three times with AcOEt. The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was then purifiedby silica gel chromatography to afford1-(6-cyclopropyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (400mg, 27%). LC-MS (m/z) 263.0 (MH+). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.59(d, J=2.5 Hz, 1 H), 7.64 (dd, J=8.3, 2.5 Hz, 1 H), 7.19 (d, J=8.3 Hz, 1H), 2.00-2.39 (m, 9 H), 0.99-1.06 (m, 4 H).

1-(6-Ethoxy-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile

Sodium metal (229 mg, 9.96 mmol) was added to ethanol (5 mL) at roomtemperature. To this solution was added1-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (300 mg,1.00 mmol) and the reaction was heated at 70° C. for 6 hours. Aftercooling to room temperature the volatiles were removed under reducedpressure. The residue was diluted with water and extracted with AcOEt(2×50 mL). The combined organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography to afford1-(6-ethoxy-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (130 mg,49%). LC-MS (m/z) 241.4 (MH⁺). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.30 (d,J=2.7 Hz, 1 H), 7.66 (dd, J=8.8, 2.7 Hz, 1 H), 6.78 (d, J=8.8, Hz, 1 H),4.38 (q, J=7.1, Hz, 2 H), 2.07-2.42 (m, 8 H), 1.41 (t, J=7.1, Hz, 3 H).

1-(6-Methoxy-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile wasprepared analogously to1-(6-Ethoxy-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile

1-[5-(1-Aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-ethanol

Step 1: 1-(6-Acetyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile

To a microwave vial was added1-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (276 mg,0.918 mmol), tributyl(1-ethoxyvinyl)tin (663 mg, 1.84 mmol), copperiodide (26.2 mg, 0.138 mmol), PdCl₂(PPh₃)₂ (32.2 mg, 0.0459 mmol) andacetonitrile (7.3 mL). The vial was purged under nitrogen, capped thenheated in an oil bath at 80° C. for 16 hours. After cooling to roomtemperature the crude reaction mixture was filtered through celite withacetonitrile and the volatiles were then removed under reduced pressure.The residue obtained was dissolved in 1,4-dioxane (20 mL), treated with1.5 N aqueous HCl (20 mL) and stirred vigorously at room temperature for1.5 hours. The mixture was then made basic by adding solid potassiumcarbonate and transferred to a 250-mL separatory funnel with water (50mL). The aqueous layer was extracted with AcOEt (3×50 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue obtainedwas treated with a saturated solution of potassium fluoride in methanol(6 mL), stirred for a few minutes, diluted with DCM, adsorbed ontosilica gel and purified by silica gel chromatography to afford1-(6-acetyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile as awhite solid (178 mg, 73%). LC-MS (m/z) 265.0 (MH⁺); t_(R)=1.21. ¹H NMR(300 MHz, CDCl₃) δ ppm 8.86 (d, J=2.0 Hz, 1 H), 8.09 (dd, J=8.3, 0.5 Hz,1 H), 7.95 (dd, J=8.3, 2.5 Hz, 1 H), 2.73 (s, 3 H), 2.46-2.14 (m, 8 H).

Step 2 and 3:1-[5-(1-Aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-ethanol

To a solution of1-(6-acetyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (80 mg,0.30 mmol) in THF (4.0 mL) at room temperature was added sodiumborohydride (23 mg, 0.60 mmol) and the reaction was stirred at roomtemperature for 2.5 hours. The reaction was quenched with methanol andthe volatiles were then removed under reduced pressure. The residue wastaken up in AcOEt (about 10 mL) and washed with saturated aqueous sodiumbicarbonate (about 10 mL). The layers were separated and the aqueouslayer was extracted again with AcOEt (2×5 mL). The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was then dissolved in a7 N ammonia solution in methanol (6.7 mL) and treated with the tip of aspatula of Raney-nickel. The flask was purged three times then left tostir under one atmosphere of hydrogen for 15 hours. The catalyst wasremoved by filtration through celite and washed with methanol. Thesolvent was then removed under reduced pressure to afford1-[5-(1-aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-ethanol as awhite solid (64 mg, 78%). LC-MS (m/z) 271.1 (MH⁺); t_(R)=0.55.

2-[5-(1-Aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-propan-2-ol

Step 1:4,4-Difluoro-1-[6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-cyclohexanecarbonitrile

A solution of1-(6-acetyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (17 mg,0.064 mmol) in THF (1.2 mL) was cooled at −50° C. and treated with a 3.0M solution of methylmagnesium bromide in ether (110 μL, 0.32 mmol).After stirring at −50° C. for 3 hours, the reaction was quenched byadding saturated aqueous ammonium chloride (5 mL) and stirred at roomtemperature for a few minutes. AcOEt (5 mL) was added and the biphasicmixture was stirred vigorously for a few seconds. The layers wereseparated and the aqueous layer was extracted again with AcOEt (5 mL).The combined organic layers were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was then purified bypreparative TLC, eluting with 60% AcOEt in hexanes to afford4,4-difluoro-1-[6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-cyclohexanecarbonitrileas a colorless oil (8.7 mg, 48%). LC-MS (m/z) 280.0 (MH⁺); t_(R)=1.11.

Step 2:2-[5-(1-Aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-propan-2-ol

Reduction of the cyano group was performed following the same procedureused in the preparation of1-[5-(1-aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-ethanol. Thesolvent was removed under reduced pressure to afford2-[5-(1-aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-propan-2-olas a colorless oil (8.8 mg, 100%). LC-MS (m/z) 285.1 (MH⁺); t_(R)=0.61.

3-cyclopropyl-2-(6-(1-ethoxyvinyl)pyridin-3-yl)propanenitrile

A solution of 2-(6-chloropyridin-3-yl)-3-cyclopropylpropanenitrile (1.0g, 4.86 mmol), tributyl(1-ethoxyvinyl)stannane (3.4 g, 9.72 mmol), LiCl(0.612 g, 14.58 mmol) and Pd(PPh₃)₄ (0.282 mg, 0.243 mmol) in1,4-dioxane (20 mL) was degassed and heated to 120° C. under N₂overnight. The reaction mixture was diluted with water and extractedwith EtOAc (3×30 mL). The combined organic layers were dried over Na₂SO₄and concentrated to give3-cyclopropyl-2-(6-(1-ethoxyvinyl)pyridin-3-yl)propanenitrile (2 g),which was used for the next step without further purification.

2-(6-acetylpyridin-3-yl)-3-cyclopropylpropanenitrile

A solution of3-cyclopropyl-2-(6-(1-ethoxyvinyl)pyridin-3-yl)propanenitrile (2 g,crude) in THF (10 mL) was added 4N HCl (10 mL) and stirred at roomtemperature for 2 h. The reaction mixture was adjusted pH to 6˜7 by 4Maq.NaOH and extracted with EtOAc (3×20 mL). The combined organic layerswere dried over Na₂SO₄ and concentrated. The crude product was purifiedby column chromatography on silica gel (EtOAc:Petroleum ether=1:10) togive 2-(6-acetylpyridin-3-yl)-3-cyclopropylpropanenitrile (600 mg,yield: 60%) ¹H NMR (CDCl₃ varian 400): δ8.58-8.51 (m, 1H), 7.95 (d,J=8.0 Hz, 1H), 7.75 (dd, J=8.0 Hz, 2.4 Hz, 1H), 3.92-3.85 (m, 1H), 2.61(s, 3H), 1.88-1.79 (m, 1H), 1.71-1.65 (m, 1H), 0.75-0.67 (m, 1H),0.49-0.45 (m, 2H), 0.10-0.03 (m, 2H).

3-cyclopropyl-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)propanenitrile

A solution of 2-(6-acetylpyridin-3-yl)-3-cyclopropylpropanenitrile (520mg, 2.43 mmol) in THF (6 mL) was added MeMgBr (0.89 mL, 2.67 mmol, 3M inEt₂O) at 0° C. under N₂ and stirred at room temperature for 2 h. Thesolution was quenched with water and extracted with EtOAc (3×20 mL). Theorganic layer was dried over Na₂SO₄ and concentrated. The crude productwas purified by column chromatography on silica gel (EtOAc:Petroleumether=1:10) to give3-cyclopropyl-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)propanenitrile(200 mg, yield: 35.6%). ¹H NMR (CDCl₃ varian 400): δ8.41 (d, J=2.4 Hz,1H), 7.67 (dd, J=8.0 Hz, 2.4 Hz, 1H), 7.36 (dd, J=8.4 Hz, 0.8 Hz, 1H),4.62 (s, 1H), 3.90-3.82 (m, 1H), 1.90-1.83 (m, 1H), 1.75-1.68 (m, 1H),1.48 (s, 6H), 0.81-0.73 (m, 1H), 0.55-0.50 (m, 2H), 0.15-0.09 (m, 2H).

[4-(4-Trifluoromethyl-phenyl)-tetrahydro-pyran-4-yl]-methylamine

To a solution of4-(4-trifluoromethyl-phenyl)-tetrahydro-pyran-4-carbonitrile (1.11 g,4.35 mmol) in methanol (54 mL) and 7N ammonia in methanol (6 mL) wasadded Raney-Nickel (300 mg). The mixture was purged 3 times withhydrogen gas then left to stir under 1 atmosphere of hydrogen at roomtemperature overnight. The crude reaction mixture was filtered throughcelite, washed with methanol and the filtrate concentrated under reducedpressure to yield the title compound (1.07 g, yield: 95%) as a whitesolid. ¹H NMR (CDCl₃ 300 MHz): δppm 7.67 (d, 2H), 7.45 (d, 2H),3.90-3.79 (m, 2H), 3.61-3.50 (m, 2H), 2.90 (s, 2H), 2.24-2.12 (m, 2H),2.00-1.88 (m, 2H), 0.87 (bs, 2H).

The following intermediates were prepared in a similar way:

-   [4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine;-   (1-(pyridin-3-yl)cyclopentyl)methanamine;-   (4-(4-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-yl)methanamine;-   4-Methyl-2-(6-methylpyridin-3-yl)-pentylamine (hydrogenation at 50    psi overnight);-   C-[4-(6-Methylpyridin-3-yl)-tetrahydropyran-4-yl]methylamine;-   3-Cyclopropyl-2-(2,6-dimethyl-pyridin-3-yl)-propylamine;-   C-[4,4-Difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine;-   3-Cyclopropyl-2-(6-fluoro-pyridin-3-yl)-propylamine;-   C-[1-(6-Methoxy-pyridin-3-yl)-4,4-difluoro-cyclohexyl]-methylamine;-   C-[1-(6-Ethoxy-pyridin-3-yl)-4,4-difluoro-cyclohexyl]-methylamine;-   C-[1-(6-Cyclopropyl-pyridin-3-yl)-4,4-difluoro-cyclohexyl]-methylamine;-   2-(6-Cyclopropyl-pyridin-3-yl)-3-(1-difluoromethyl-cyclopropyl)-propylamine    (hydrogenation at 30 psi overnight);-   2-(6-Cyclopropyl-pyridin-3-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine    (hydrogenation at 50 psi for 12 h);-   3-Cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine;-   C-[4-(6-trifluoromethylpyridin-3-yl)-tetrahydropyran-4-yl]-methylamine    (hydrogenation at 45 psi for 3 h);-   C-[4,4-Difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine    (hydrogenation at 50 psi overnight);-   3-(1-Difluoromethyl-cyclopropyl)-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine    (hydrogenation at 50 psi overnight);-   3-(1-Trifluoromethyl-cyclopropyl)-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine    (hydrogenation at 50 psi overnight);-   C-[4,4-Difluoro-1-(2-methyl-pyrimidin-5-yl)-cyclohexyl]-methylamine    (hydrogenation at 30 psi for 2 h);-   3-Cyclopropyl-2-(2-methyl-pyrimidin-5-yl)-propylamine (hydrogenation    at 30 psi for 30 min);-   2-(2-Methyl-pyrimidin-5-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine    (hydrogenation at 50 psi for 30 min);-   3-Cyclopropyl-2-(2-trifluoromethyl-pyrimidin-5-yl)-propylamine    (hydrogenation at 50 psi for 30 min);-   2-(2-(Trifluoromethyl)pyrimidin-5-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine;-   2-(2-(Trifluoromethyl)pyrimidin-5-yl)-3-(1-difluoromethyl-cyclopropyl)-propylamine;-   [4,4-Difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl]methanamine;-   3-Cyclopropyl-2-(5-methyl-pyrazin-2-yl)-propylamine;

[1-(4-Methoxyphenyl)-cyclopentyl]-methylamine

To a stirred solution of 1-(4-Methoxyphenyl)-1-cyclopentanecarbonitrile(4.02 g, 20 mmol) in THF (50 mL) cooled to 0° C. was added lithiumaluminium hydride (1.52 g, 40 mmol) and the reaction was allowed to warmto room temperature and stirred for 16 h. To the reaction mixture wasadded cautiously water (2.0 mL) then 2N NaOH (aq) (2 mL). The mixturewas filtered and concentrated in vacuo to yield the title compound whichwas used without further purification (1.07 g, yield: 95%). ¹H NMR(CDCl₃ 300 MHz): δppm 7.12 (d, 2H), 6.80 (d, 2H), 3.71 (s, 2H), 2.62 (s,3H), 1.88-1.58 (m, 8H).

The following intermediates were prepared in a similar way:

-   [4-(4-Chloro-phenyl)-1-methyl-piperidine-4-yl]-methylamine;-   (1-methyl-4-phenylpiperidin-4-yl)methanamine;-   3-(4-Chloro-phenyl)-N1,N1-dimethyl-butane-1,4-diamine;

2-Cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine

A solution of Cyclopropyl-(6-trifluoromethyl-pyridin-3-yl)-acetonitrile(93 mg, 0.41 mmol) in THF (2.8 mL) in a 5 mL microwave vial was treatedwith borane-methyl sulfide complex (0.51 mL, 5.4 mmol). The reactionvessel was capped and the mixture was heated in the microwave reactorfor 20 mins at 100° C. The reaction mixture was concentrated in vacuo toyield the crude title compound which was used without furtherpurification (95 mg, purity: 73%, yield: 73%). LCMS (MH+): m/z=231.1,t_(R) (minutes, Method D)=0.40

The following intermediates were prepared in a similar way:

-   2-(5-Chloro-pyridin-3-yl)-3-cyclopropyl-propylamine;

4,4-difluoro-1-(4-methyl-1H-imidazol-1-yl)cyclohexanecarboxylic acid

4-methylimidazole (1.67 g, 20.3 mmol) was dissolved in THF (200 mL, 2000mmol). Powdered sodium hydroxide (4.19 g, 104.8 mmol) was added togetherwith 4,4-difluorocyclohexanone (2.90 g, 22 mmol). Chloroform (7.9 mL, 99mmol) was added dropwise and the reaction was stirred overnight at roomtemperature.

The reaction was acidified with 2M HCl and filtered. The solid wastreated with MeOH, to dissolve the product and leave back NaCl. Thereaction was filtered again and the residue was concentrated to give thetitle compound as the hydrochloride salt (3.498 g, 58%).

ethyl 4,4-difluoro-1-(4-methyl-1H-imidazol-1-yl)cyclohexanecarboxylate

4,4-Difluoro-1-(4-methyl-imidazol-1-yl)-cyclohexanecarboxylic acid;hydrochloride (662 mg, 1.18 mmol) was dissolved in THF (20 mL, 200 mmol)and cooled in ice. N,N-Diisopropylethylamine (0.850 mL, 4.88 mmol) wasadded dropwise over 5 minutes at 5-10° C. The mixture was stirred for 15minutes. Ethyl chloroformate (0.150 mL, 1.57 mmol) was added dropwiseover 5 minutes at 5-7° C. The mixture was stirred 50 minutes at 5° C.Then warmed to room temperature. After 1 hour the reaction wasconcentrated down and the residue was purified by flash columnchromatography on silica gel (eluding w a gradient elution from heptaneto AcOEt) to give the title compound (199 mg, 59%) ¹H NMR (CDCl₃ 500MHz): δppm 7.59 (s, 1H), 6.76 (s, 1H), 4.20 (m, 2H), 2.61 (m, 2H), 2.43(m, 2H), 2.24 (s, 3H), 2.03 (m, 4H), 1.22 (m, 3H).

4,4-difluoro-1-(4-methyl-1H-imidazol-1-yl)cyclohexanecarboxamide

4,4-Difluoro-1-(4-methyl-imidazol-1-yl)-cyclohexanecarboxylic acid ethylester (199 mg, 0.731 mmol was dissolved in 7 M ammonia in methanol (5mL) and stirred for 72 hours. The sample was concentrated and theresidue was purified by flash column chromatography on silica gel(eluding w a gradient elution from heptane to AcOEt to 5% Et₃N/10%MeOH/85% AcOEt) to give the title compound (84 mg, 45%) ¹H NMR (CDCl₃500 MHz): δppm 7.64 (s, 1H), 6.82 (s, 1H), 5.17 (m, 2H), 2.68 (m, 2H),2.41 (m, 2H), 2.30 (s, 3H), 2.23 (m, 2H), 1.85 (m, 2H).

(4,4-difluoro-1-(4-methyl-1H-imidazol-1-yl)cyclohexyl)methanamine

Into a round bottom flask was added4,4-Difluoro-1-(4-methyl-imidazol-1-yl)-cyclohexanecarboxylic acid amide(99 mg, 0.39 mmol) and THF (10 mL, 100 mmol) at room temperature, to thereaction mixture was added lithium tetrahydroaluminate (365 mg, 9.62mmol). The reaction was refluxed for 6 hours, before being quenched withwater (0.4 ml), 2M NaOH (0.4 ml) and water (0.8 ml). The reactionmixture was filtered and conc. The residue was purified by flash columnchromatography on silica gel (eluding w a mixture of 5% Et₃N/10%MeOH/85% AcOEt) to give the title compound (44 mg, 47%). ¹H NMR (CDCl₃500 MHz): δppm 7.55 (s, 1H), 6.71 (s, 1H), 2.70 (s, 2H), 2.4-1.7 (m,8H), 2.21 (s, 3H).

3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propanenitrile

To a solution of3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propanenitrile (310mg, 1.29 mmol) and MeI (0.27 g, 1.9 mmol) in dioxane (10 ml) was addedt-BuOK (1.39 mL, 1.39 mmol, 1M in THF) dropwise at room temperatureunder N₂. The mixture was stirred for 1 h, then quenched by sat.aq.NH₄Cl (10 mL), and extracted with EtOAc (3×10 ml). The organic layer wasconcentrated under reduced pressure to give crude product, which waspurified by column chromatography on silica gel (EtOAc/Petroleumether=1:4) to give compound the title compound (120 mg, yield: 36%). ¹HNMR (CDCl₃ varian 400): δ9.02 (s, 2H), 1.92 (d, J=6.8 Hz, 2H), 1.87 (s,3H), 0.80-0.67 (m, 1H), 0.65-0.56 (m, 1H), 0.55-0.45 (m, 1H), 0.30-0.20(m, 1H), 0.05-0.04 (m, 1H).

3-Cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)-2-methylpropan-1-amine

A solution of 2-(pyrimidin-5-yl)acetonitrile (1.8 g, 15.1 mmol) in DMF(20 mL) was degassed and (bromomethyl)cyclopropane was added (2.04 g,15.1 mmol). The reaction mixture was cooled to −10° C., NaH was added(720 mg, 18.1 mmol, 60% in mineral oil) in portions under N₂ and stirredat the same temperature for 45 mins. The reaction mixture was quenchedwith sat. NH₄Cl and extracted with EtOAc (30 ml×3). The organic layerwas washed with brine, dried over Na₂SO₄ and concentrated. The crudeproduct was purification by column chromatography on silica gel(petroleum ether: EtOAc=3:1) to give3-cyclopropyl-2-(pyrimidin-5-yl)propanenitrile (2.25 g, yield: 85%). ¹HNMR (CDCl₃ 400 MHz): δ9.22 (s, 1H), δ8.78 (s, 2H), 3.80 (t, J=8 Hz, 2H),1.98-1.92 (m, 1H), 1.83-1.79 (m, 1H), 0.87-0.83 (m, 1H), 0.61-0.59 (m,2H), 0.21-0.13 (m, 2H).

The following intermediate was prepared in a similar way:

-   2-(Pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile;-   2-(5-chloropyridin-3-yl)-3-cyclopropylpropanenitrile;-   3-cyclopropyl-2-(pyrimidin-5-yl)propanenitrile;-   3-(1-fluorocyclopropyl)-2-(pyrimidin-5-yl)propanenitrile;

To a solution of 3-cyclopropyl-2-(pyrimidin-5-yl)propanenitrile (1.5 g,8.67 mmol) and MeI (1.45 g, 13.0 mmol) in 1,4-dioxane (20 ml) was addedt-BuOK (9.57 ml, 9.57 mmol) dropwise at room temperature under N₂. Themixture was stirred for 1 h at room temperature then quenched by sat.aqNH₄Cl (20 ml) and extracted with EtOAc (3×30 ml). The organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure to give3-cyclopropyl-2-methyl-2-(pyrimidin-5-yl)propanenitrile (1.5 g), whichwas used directly for next step.

The following intermediate was prepared in a similar way:

-   3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propanenitrile;

3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)-2-methylpropanenitrile

To a solution of 3-cyclopropyl-2-methyl-2-(pyrimidin-5-yl)propanenitrile(2.5 g, 13.4 mmol) and DMFS (7.8 g, 26.7 mmol) in DCM (40 ml) and H₂O(12 ml) at room temperature was added TFA (1.5 g, 13.4 mmol) followed byslow addition of t-BuOOH (8.6 g, 67 mmol) with vigorous stirring. Thereaction mixture was stirred at room temperature overnight. To thereaction mixture was added additional DMFS (7.8 g, 26.7 mmol) andt-BuOOH (8.6 g, 67 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was added aq. NaHCO₃ andextracted with EtOAc (3×50 ml). The organic layer was dried over Na₂SO₄and concentrated. The crude product was purification by columnchromatography on silica gel (petroleum ether:EtOAc=4:1) to give3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)-2-methylpropanenitrile(1.1 g, yield: 35%). ¹H NMR (CDCl₃ 400 MHz): δ8.97 (s, 2H), 6.82-6.55(m, 1H), 1.92-1.90 (m, 2H), 1.85 (s, 3H), 0.71-0.65 (m, 1H), 0.60-0.57(m, 1H), 0.51-0.47 (m, 1H), 0.26-0.20 (m, 1H), 0.03-0.00 (m, 1H).

The following intermediate was prepared in a similar way:

-   2-(2-(Difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile;-   2-(2-(Difluoromethyl)pyrimidin-5-yl)-3-(1-(fluoro)cyclopropyl)propanenitrile;-   3-cyclopropyl-2-methyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propanenitrile;-   3-cyclopropyl-2-(2-(difluoromethyl)pyridin-5-yl)propanenitrile;-   3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propanenitrile;-   3-(1-fluorocyclopropyl)-2-(2-(difluoromethyl)pyrimidin-5-yl)propanenitrile;-   3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(difluoromethyl)pyrimidin-5-yl)propanenitrile;

A mixture of3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)-2-methylpropanenitrile(1 g, 4.2 mmol) and NH₃.H₂O (3 mL) in MeOH (20 mL) was hydrogenated withRaney Ni (1.5 g) under 50 Psi for 3 h. The reaction mixture was filteredand concentrated to give3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)-2-methylpropan-1-amine(1 g), which was used directly for next step.

The following intermediates were prepared in a similar way:

-   2-(2-(Difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propan-1-amine;-   2-(2-(Difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-amine;-   (4,4-difluoro-1-(5-fluoropyridin-3-yl)cyclohexyl)methanamine;-   3-(1-fluorocyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine;-   3-(1-fluorocyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine;-   3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propan-1-amine;-   3-(1-fluorocyclopropyl)-2-(2-(difluoromethyl)pyrimidin-5-yl)propan-1-amine;-   2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-amine;-   3-cyclopropyl-2-methyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propan-1-amine;-   3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine;-   3-(1-fluorocyclopropyl)-2-(2-methylpyrimidin-5-yl)propan-1-amine;

2-(4-Chlorophenyl)-2-(dihydro-2H-pyran-4(3H)-ylidene)acetonitrile

Sodium (152 mg, 6.6 mmol) was added into EtOH (10 ml) and stirred atroom temperature for 20 minutes. 2-(4-Chlorophenyl)acetonitrile (500 mg,3.3 mmol) was added to the solution, after all the sodium had dissolved,and the reaction was stirred at room temperature for 0.5 h. To theresulting mixture was added dihydro-2H-pyran-4(3H)-one (330 mg, 3.3mmol) and stirred at room temperature for 1.5 h. The solvent wasremoved. To the residue was added water and extracted with EtOAc (3×20mL). The combined organic solution were dried over Na₂SO₄ andconcentrated to give crude product, which was purified by flash columnchromatography (petroleum ether:EtOAc=10:1) to give compound2-(4-chlorophenyl)-2-(dihydro-2H-pyran-4(3H)-ylidene)acetonitrile (300mg) which was used for the next step without further purification.

2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine

A mixture of2-(4-chlorophenyl)-2-(dihydro-2H-pyran-4(3H)-ylidene)acetonitrile (200mg, 0.85 mmol) and NH₃.H₂O (2 mL) in MeOH (30 mL) was hydrogenated withRaney Ni (500 mg) under H₂ (50 Psi) overnight. The reaction mixture wasfiltered and concentrated to give2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine (190 mg, 93%).¹H NMR (CDCl₃ 400 MHz): δ7.39-7.29 (m, 2H), 7.19-7.09 (m, 2H), 4.03-3.95(m, 1H), 3.89-3.80 (m, 1H), 3.51-3.45 (m, 2H), 3.40-3.32 (m, 1H),3.30-3.20 (m, 1H), 2.61-2.49 (m, 2H), 1.82-1.69 (m, 2H), 1.49-1.31 (m,1H), 1.29-1.10 (m, 2H).

The following intermediates were prepared in a similar way:

-   2-(2-Methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine;-   2-(Tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine;

2-(4-Hydroxytetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile:

2-(6-(Trifluoromethyl)pyridin-3-yl)acetonitrile (260 mg, 1.4 mmol) wasdissolved in THF (3 mL, 30 mmol) under Ar and cooled at −78° C. Asolution of 0.6 M sodium bis(trimethylsilyl)amide in toluene (3.49 mL)was added dropwise. After stirring at −78° C. for 4 hours the reactionwas allowed to reach −50° C. for 30 minutes. Thentetrahydro-4H-pyran-4-one (0.189 mL, 2.10 mmol) was added dropwise at−60° C. and the reaction was kept at this temperature for 45 minutes. Tothe reaction was added sat. aq. NH₄Cl (10 mL) and it was extracted AcOEt(3×20 mL). The combined organic phases were washed with brine, driedover MgSO₄ and concentrated in vacuo. The crude product was purified byflash chromatography to yield2-(4-Hydroxytetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile(189 mg, 0.660 mmol, 47%).

¹H NMR (600 MHz, DMSO) δ 8.72 (d, J=1.9 Hz, 1H), 8.08 (dd, J=8.1, 2.0Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 4.56 (s, 1H), 3.78-3.68 (m, 1H),3.67-3.61 (m, 1H), 3.59-3.52 (m, 1H), 3.44 (td, J=11.7, 2.3 Hz, 1H),1.81-1.72 (m, 1H), 1.73-1.60 (m, 2H), 1.04 (dd, J=13.4, 2.3 Hz, 1H).

2-(Dihydro-2H-pyran-4(3H)-ylidene)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile

(4-Hydroxy-tetrahydro-pyran-4-yl)-(6-trifluoromethyl-pyridin-3-yl)-acetonitrile(1.15 g, 4.02 mmol) was dissolved in thionyl chloride (50 mL, 600 mmol).One drop of DMF was added and the mixture was heated at reflux for 1hour and then cooled to room temperature and concentrated in vacuo. Theresulting crude product was purified by flash chromatography to yield2-(dihydro-2H-pyran-4(3H)-ylidene)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile(1.04 g, 3.9 mmol, 95%).

¹H NMR (600 MHz, CDCl₃) δ 8.68 (d, J=2.1 Hz, 1H), 7.89 (ddd, J=8.1, 2.2,0.5 Hz, 1H), 7.80 (dd, J=8.1, 0.7 Hz, 1H), 3.93 (t, J=5.5 Hz, 2H), 3.74(t, J=5.5 Hz, 2H), 2.94-2.86 (m, 2H), 2.52 (t, J=5.5 Hz, 2H).

2-(Tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine

2-(Dihydro-2H-pyran-4(3H)-ylidene)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile(1.04 g, 3.88 mmol) was dissolved in methanol (50 mL) and 7 M NH₃ inmethanol (20 mL) was added. The solution was flushed with Ar. Raneynickel (0.033 g, 0.39 mmol) was added and mixture hydrogenated on a ParrApparatus at room temperature for 4 hours. Then filtered through a plugof celite and concentrated in vacuo. The crude product was used for thenext step without further purification.

LC-MS (m/z) 275.2 (MH⁺), t_(R)(minutes, Method E)=0.33.

2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)acetonitrile

A solution of 2-(2-methylpyrimidin-5-yl)acetonitrile (1.0 g, 7.51 mmol)and 4-chloropyridine hydrochloride (1.13 g, 7.51) in dioxane (20 mL) ina dried flask was degassed and filled with nitrogen. t-BuOK (18.8 mL, 1Min THF) was added. The mixture was stirred at 100° C. for 4 h and cooledto room temperature, quenched by cooled sat. aq. NH₄Cl (20 mL). Theresulting mixture was extracted with EtOAc (3×10 mL). The combinedorganic layers were washed with brine (3×10 mL), dried over Na₂SO₄,concentrated under reduced pressure to give the crude product, which waspurified by column chromatography on silica gel (MEOH:EtOAc=1:10) togive 2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)acetonitrile (700 mg,crude).

2-(pyridin-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile

A dried flask was charged with2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (1.0 g, 5.38 mmol) inDME (20 ml). The mixture was degassed and filled with N₂, then t-BuOK(30 ml, 30 mmol, 1M in THF), 4-bromopyridine hydrochloride (2.1 g, 10.7mmol) and Pd(dppf)Cl₂ (39.6 mg, 0.538 mmol) was added. The mixture wasstirred at 60° C. for 3 h. After cooling to room temperature, sat.aqNH₄Cl (15 ml) was added and the solution was extracted with EtOAc (3×30ml). The combined organic layers were washed with brine and dried overNa₂SO₄, concentrated in vacuo. The residue was purified by columnchromatography on silica gel (EtOAc:Petroleum ether=4:1) to give2-(pyridin-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (360mg, yield: 25.7%). ¹H NMR (CDCl₃400 MHz): δ8.75 (d, J=1.6 Hz, 1H), 8.71(d, J=6.0 Hz, 2H), 7.90 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.77 (d, J=8.4 Hz,1H), 7.31 (d, J=6.0 Hz, 2H), 5.26 (s, 1H).

2-(pyridin-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine

A mixture of2-(pyridin-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (360mg, 1.36 mmol) and NH₃.H₂O (2 mL) in MeOH (30 mL) was hydrogenated withRaney Ni (700 mg) under H₂ (50 Psi) for 5 h. The reaction mixture wasfiltered and concentrated to give2-(pyridin-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine (300 mg),which was used in the next step without further purification.

The following intermediates were prepared in a similar way:

-   2-(Pyridin-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine;-   2-Phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine;-   2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamine;-   2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine;-   2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyrimidin-3-yl)ethanamine;-   2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine;

2-(4,4-difluorocyclohexylidene)-2-(2-methylpyrimidin-5-yl)acetonitrile

To a solution of 2-(2-methylpyrimidin-5-yl)acetonitrile (1 g, 7.52 mmol)and 4,4-difluorocyclohexanone (1.1 g, 8.27 mmol) in 1,4-dioxane (40 mL)was added t-BuOK (0.8 g, 8.27 mmol) in two portions. After the additionwas completed, the reaction was heated to 60° C. and stirred overnight.The reaction solution was cooled to 0° C., quenched by saturated NH₄Claq. solution and extracted with EtOAC (50 m×3). The combined organiclayer was washed with brine, dried over Na₂SO₄ and concentrated to getthe crude product, which was purified by column chromatography on silicagel (Petroleum ether:EtOAc=4:1˜2:1) to afford2-(4,4-difluorocyclohexylidene)-2-(2-methylpyrimidin-5-yl)acetonitrile(440 mg, yield: 23.5%). ¹H NMR (CDCl3 varian 400 MHz): δ8.61 (s, 2H),2.97 (t, J=8.0 Hz, 2H), 2.80 (s, 3H), 2.55 (t, J=8.0 Hz, 2H), 2.27-2.17(m, 2H), 2.09-1.98 (m, 2H).

2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine

A mixture of2-(4,4-difluorocyclohexylidene)-2-(2-methylpyrimidin-5-yl)acetonitrile(290 mg, 0.57 mmol), Raney-Ni (1.5 g), NH₃.H₂O (2 mL) in MeOH (30 mL)was degassed and purged with nitrogen and H₂ each 3 times. The mixturewas stirred at room temperature under H₂ (50 psi) for 4 h. The resultingmixture was filtered through the celite. The filtrate was concentratedunder reduced pressure to give2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine (280 mg,crude), which was used in the next step without further purification.

The following intermediates were prepared in a similar way:

-   2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine;

2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile

A solution of 2-(4-fluorophenyl)acetonitrile (2 g, 14.8 mmol) in DME (50mL) was degassed. KOtBu (6.63 g, 59.2 mmol) was added in portions. Afteraddition was completed, the mixture was stirred for 5 min at roomtemperature and a brown suspension was formed. Then5-bromo-2-(trifluoromethyl)pyridine (6.69 g, 29.6 mmol) was addedfollowed by Pf(dppf)C₁₂ (1.35 g, 1.48 mmol). The resulting mixture washeated to 60° C. for 4 h. The reaction mixture was cooled to roomtemperature and quenched by aq. NH4Cl to pH=5˜6. The mixture wasextracted with EtOAc (50 mL×3). The combined organic layer was washedwith brine, dried over Na2SO4 and concentrated. The residue was purifiedby flash combi (Petroleum ether/EtOAc=15:1) to give2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (18g, ˜70% purity+350 mg, pure, yield: 51.8%). ¹H NMR (CDCl3 400 MHz) δ8.98(s, 1H), 7.89 (dd, J=8.4, 2.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.40-7.30(m, 2H), 7.20-7.10 (m, 2H), 5.26 (s, 1H).

The following intermediates were prepared in a similar way:

-   2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)acetonitrile;-   2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile;

methyl5-cyano-2-hydroxy-5-(2-methylpyrimidin-5-yl)cyclohex-1-enecarboxylate

A solution of 2-(2-methylpyrimidin-5-yl)acetonitrile (4 g, 0.03 amol)and methyl acrylate (5.69 g, 0.066 mol) in THF (60 mL) was added t-BuOK(93 mL, 0.093 mol, 1M in THF) and stirred at room temperature for 4 h.The reaction mixture was quenched by sat. NH₄Cl and extracted with EtOAc(3×150 mL). The organic layer was dried over Na₂SO₄ and concentrated togive methyl5-cyano-2-hydroxy-5-(2-methylpyrimidin-5-yl)cyclohex-1-enecarboxylate(5.5 g), which was used for the next step directly.

1-(2-methylpyrimidin-5-yl)-4-oxocyclohexanecarbonitrile

A solution of methyl5-cyano-2-hydroxy-5-(2-methylpyrimidin-5-yl)cyclohex-1-enecarboxylate(6.2 g, 0.023 mol), NaCl (1.46 g, 0.025 mol) and H₂O (1.24 mL, 0.069mol) in DMSO (50 mL) was heated to 160° C. for 3 h. After cooling toroom temperature, the reaction was added water and extracted with EtOAc(6×100 mL). The organic layer was washed with brine, dried over Na₂SO₄and concentrated. The crude product was purified by flash chromatography(EtOAc:Petroleum ether=1:3˜3:2) to give1-(2-methylpyrimidin-5-yl)-4-oxocyclohexanecarbonitrile (2 g, yield:41%). ¹H NMR (CDCl₃400 MHz): δ8.80 (s, 2H), 3.00-2.90 (m, 2H), 2.77 (s,3H), 2.70-2.60 (m, 2H), 2.60-2.50 (m, 2H), 2.40-2.25 (m, 1H).

4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexanecarbonitrile

A solution of 1-(2-methylpyrimidin-5-yl)-4-oxocyclohexanecarbonitrile(2.0 g, 9.3 mmol), XtalFlour-E (4.69 g, 20.47 mmol) and Et₃N3HF (4.79 g,29.76 mmol) in DCM (40 mL) was stirred at room temperature overnight.The reaction mixture was quenched by sat. NaHCO₃ and extracted with DCM(3×50 mL). The organic layer was dried over Na₂SO₄ and concentrated. Thecrude product was purified by flash column chromatography to give4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexanecarbonitrile (1.2 g,yield: 54%), which was not pure and used directly for next step.

4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxylic acid

To a mixture of4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexanecarbonitrile (1.2 g,5.1 mmol) in MeOH/H₂O (20 mL, 1:1) was added NaOH (612 mg, 15.3 mmol)and heated to 100° C. overnight. The MeOH was removed in vacuo. Theaqueous layer was extracted with EtOAc (3×30 mL) and the organic layerswas discarded. The aqueous layer was adjusted pH to 3˜4 with 3N HCl andextracted with EtOAc (3×30 mL). The organic layer was dried over Na₂SO₄and concentrated to give4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxylic acid (1.2g, yield: 92%). ¹H NMR (CDCl₃400 MHz): δ8.81 (s, 2H), 2.80-2.60 (m, 5H),2.20-2.00 (m, 6H).

4,4-difluoro-N-methoxy-N-methyl-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxamide

A solution of4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxylic acid (1.2g, 4.68 mmol), N,O-dimethylhydroxylamine hydrochloride (456 mg, 4.68mmol), HOBt (759.33 mg, 5.62 mmol), EDCI.HCl (1.08 g, 5.62 mmol) andDIPEA (3.23 mL, 18.73 mmol) in DMF (20 mL) was stirred at roomtemperature. The reaction mixture was added water and extracted withEtOAc (3×50 mL). The organic layer was washed with brine, dried overNa₂SO₄ and concentrated to give4,4-difluoro-N-methoxy-N-methyl-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxamide(380 mg), which was used for the next step directly. About 0.9 g of4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxylic acid wasrecycled.

1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone

A solution of4,4-difluoro-N-methoxy-N-methyl-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxamide(700 mg, 2.34 mmol) in THF (20 mL) was added MeMgBr (11.7 mL, 35.12mmol, 3M in Et₂O) at 0° C. and stirred at room temperature for 4 h. Thereaction mixture was quenched by saturated NH₄Cl at 0° C. and extractedwith EtOAc (2×50 mL). The organic layer was washed with brine, driedover Na₂SO₄ and concentrated to give crude product, which was purifiedby flash chromatography (EtOAc: petroleum ether=1:3˜3:2) to give1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone (350 mg,yield: 59%). ¹H NMR (CDCl₃ 400 MHz): δ8.58 (s, 2H), 2.73 (s, 3H),2.55-2.45 (m, 2H), 2.20-1.85 (m, 9H).

(Z)-1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone oxime

A mixture of1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone (350 mg,1.38 mmol), NH₂OH.HCl (143.7 mg, 2.07 mmol) and NaOH (165.6 mg, 4.14mmol) in EtOH/H₂O (16 mL, 1:1) was heated to 80° C. overnight. The EtOHwas removed. The residue was extracted with EtOAc (2×20 mL). The organiclayer was dried over Na₂SO₄ and concentrated to give(Z)-1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone oxime(320 mg), which was used for the next step directly.

1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanamine

A mixture of(Z)-1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone oxime(320 mg, 1.19 mmol) and aq.NH₃ (2 mL) was hydrogenated with Raney Ni(300 mg) under H₂ (50 Psi) for 3 h. The reaction mixture was filteredand concentrated. The residue was dissolved in EtOAc (15 mL), dried overNa₂SO₄ and concentrated to give1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanamine (300mg), which was used for the next step directly.

4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carbonitrile

A solution of 2-(2-methylpyrimidin-5-yl)acetonitrile (4 g, 0.03 amol)and 1-bromo-2-(2-bromoethoxyl)ethane (7.66 g, 0.033 mol) in 1,4-dioxane(60 mL) was added t-BuOK (66 mL, 0.066 mol, 1M in THF) and heated to 80°C. for 4 h. The reaction mixture was cooled to room temperature,quenched by sat.NH₄Cl. The 1,4-dioxane was removed under reducedpressure. The residue aqueous layer was extracted with EtOAc (3×150 mL).The organic layer was dried over Na₂SO₄ and concentrated to give4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carbonitrile (5.5 g,yield: 90.5%). ¹H NMR (CDCl₃ 400 MHz): δ8.75 (s, 2H), 4.15-4.05 (m, 2H),3.95-3.85 (m, 2H), 2.75 (s, 3H), 2.15-2.00 (m, 4H).

4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carboxylic acid

A mixture of4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carbonitrile (5.5 g,0.027 mol) in MeOH/H₂O (60 mL, 1:1) was added NaOH (3.25 g, 0.081 mol)and heated to 100° C. overnight. The MeOH was removed in vacuo. Theaqueous layer was extracted with EtOAc (2×30 mL) and the organic layerswas discarded. The aqueous layer was adjusted pH to 2˜3 with 3N HCl andextracted with EtOAc (6×50 mL). The organic layer was dried over Na₂SO₄and concentrated to give4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carboxylic acid (4.0 g,yield: 67%). ¹H NMR (DMSO-d₆ 400 MHz): δ13.04 (br, 1H), 8.71 (s, 2H),3.80-3.70 (m, 2H), 3.60-3.40 (m, 2H), 2.61 (s, 3H), 2.40-2.30 (m, 2H),2.00-1.85 (m, 2H).

N-methoxy-N-methyl-4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carboxamide

A solution of 4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carboxylicacid (4.0 g, 18.02 mmol), N,O-dimethylhydroxylamine hydrochloride (2.1g, 21.6 mmol), HOBt (2.92 g, 21.6 mmol), EDCI.HCl (4.15 g, 21.62 mmol)and DIPEA (15.6 mL, 90.1 mmol) in DMF (50 mL) was stirred at roomtemperature overnight. To the reaction mixture was added water andextracted with EtOAc (3×200 mL). The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated to give crude product, whichwas purified by flash column chromatography (EtOAc: petroleum ether=1:1)to giveN-methoxy-N-methyl-4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carboxamide(3.0 g, yield: 63%). ¹H NMR (CDCl₃ 400 MHz): δ8.55 (s, 2H), 3.90-3.75(m, 4H), 3.14 (s, 3H), 2.95 (s, 3H), 2.72 (s, 3H), 2.55-2.45 (m, 2H),2.06-1.95 (m, 2H).

1-(4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)ethanone

To a solution ofN-methoxy-N-methyl-4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carboxamide(1.0 g, 3.0 mmol, 80% purity in LC-MS) in THF (10 mL) was added MeMgBr(7.05 mL, 21.1 mmol, 3M in Et₂O) at 0° C. and stirred at roomtemperature for 3 h. The reaction mixture was quenched by saturatedNH₄Cl at 0° C. and extracted with EtOAc (3×50 mL). The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated to give crudeproduct, which was purified by flash column chromatography (EtOAc:petroleum ether=1:1) to give1-(4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)ethanone (0.3 g,yield: 69.3%). ¹H NMR (CDCl₃ 400 MHz): δ8.58 (s, 2H), 3.90-3.80 (m, 2H),3.65-3.55 (m, 2H), 2.75 (s, 3H), 2.50-2.40 (m, 2H), 2.15-2.05 (m, 2H),2.02 (s, 3H).

1-(4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)ethanamine

A mixture of1-(4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)ethanone (300 mg,1.35 mmol), saturated NH₄OAc in EtOH (15 mL) and aq.NH₃ (5 mL) was addedNaCNBH₃ (255 mg, 4.05 mmol) and heated to reflux overnight. The EtOH wasremoved. The residue was extracted with EtOAc (5×10 mL) and the organiclayer was discarded. The precipitation of solid was collected byfiltration from the aqueous layer after 16 hours to give1-(4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)ethanamine (100mg, yield: 33.3%). ¹H NMR (DMSO-d₆ 400 MHz): δ8.67 (s, 2H), 3.80-3.65(m, 2H), 3.20-3.05 (m, 2H), 2.63 (s, 3H), 2.45-2.35 (m, 1H), 2.35-2.25(m, 2H), 1.81-1.70 (m, 2H), 0.87 (d, J=6.4 Hz, 3H).

4-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)butanenitrile

A solution of 2-(2-(trifluoromethyl)pyrimidin-5-yl)acetonitrile (500 mg,2.67 mmol) and 1-bromo-2-methoxyethane (419 mg, 2.81 mmol) in1,4-dioxane (5 mL) was degassed and added t-BuOK (2.81 mL, 2.81 mmol, 1Min THF) at 0° C. The resulting mixture was stirred at room temperatureovernight. The reaction mixture was quenched by sat.NH₄Cl and extractedwith EtOAc (3×10 mL). The organic layer was dried over Na₂SO₄ andconcentrated. The crude product was purified by flash columnchromatography (EtOAc: petroleum ether=1:10) to give4-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)butanenitrile (100 mg,yield: 15%, 85% purity in LCMS, [M+H]=246).

4-Benzylpyridazine

A solution of pyridazine (2.2 g, 27.5 mmol) and 2-phenylacetic acid(18.7 g, 137.5 mmol), AgNO₃ (1.4 g, 8.25 mmol) in 2N H₂SO₄ (27.7 ml) washeated to 60-70° C. under stirring, then, a solution of (NH₄)₂S₂O₈ (18.6g, 82.5 mmol) in 80 ml of water was added within 20 minutes, Afterheating to 70-90° C. for 1.5 hour, the reaction solution was cooled toroom temperature and extracted with DCM (2×100 ml), the combined organiclayers were washed with 2N H₂SO₄ (3×70 ml), then, the combined aqueouslayer was made alkaline with 50% NaOH and extracted with DCM (3×80 ml),dried over Na₂SO₄ and concentrated to get the crude product, which waspurified by column chromatography on silica gel (petroleumEther:EtOAc=2:1) to afford 4-benzylpyridazine (1.0 g, yield: 22%). ¹HNMR (CDCl₃ 400 MHz): δ9.09 (s, 1H), 9.06 (d, J=5.2 Hz, 1H), 7.40-7.28(m, 3H), 7.25-7.20 (m, 1H), 7.18 (d, J=7.2 Hz, 2H), 4.0 (s, 2H).

Phenyl(pyridazin-4-yl)methanone

A solution of 4-benzylpyridazine (1.0 g, 5.9 mmol) in AcOH (28 mL) wasadded dropwise to a stirring suspension of SeO₂ (3.2 g, 29.5 mmol) inAcOH (28 mL), the resulting mixture was heated to 100° C. for 1 h. TLCshowed the starting material had disappeared, then the reaction solutionwas filtrated, the filtration was concentrated under reduced pressure,and Sat.aq Na₂CO₃ was added to adjust PH=9-10, then, extracted with DCM(50 mL×3), washed by brine, dried over Na₂SO₄ and concentrated to getthe phenyl(pyridazin-4-yl)methanone (1.0 g, yield: 91%). ¹H NMR (CDCl₃400 MHz): δ9.50-9.45 (m, 2H), 7.83 (d, J=7.6 Hz, 2H), 7.78-7.74 (dd,J=5.2, 2.4 Hz, 1H), 7.74-7.68 (m, 1H), 7.57 (t, J=7.2 Hz, 2H).

(E)-Ethyl 3-phenyl-3-(pyridazin-4-yl)acrylate

To a solution of ethyl 2-(diethoxyphosphoryl)acetate (1.46 g, 7.93 mmol)in THF (40 mL) was added NaH (476 mg, 11.9 mmol) in portions at 0° C.,the resulting mixture was stirred at 0° C. for 20 minutes, then, thephenyl(pyridazin-4-yl)methanone was added in portions, the resultingmixture was stirred at 0° C. for 4 hour. The LC-MS showed the MS signalof desired product was detected, then, the reaction solution was addedsat. aq. NH₄Cl at 0° C., then, extracted with AcOEt (3×50 ml), thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to get the crude product, which was purified by columnchromatography on silica gel (petroleum Ether:EtOAc=2:1) to afford(E)-ethyl 3-phenyl-3-(pyridazin-4-yl)acrylate (1.68 g, yield: 83.2%). ¹HNMR (CDCl₃ 400 MHz): δ9.25 (d, J=5.2 Hz, 1H), 9.06 (s, 1H), 7.47-7.32(m, 4H), 7.30-7.20 (m, 2H), 6.55 (s, 1H), 4.95 (q, J=7.2 Hz, 2H), 1.16(t, J=7.2 Hz, 3H).

Ethyl 3-phenyl-3-(pyridazin-4-yl)propanoate

To a solution of (E)-ethyl 3-phenyl-3-(pyridazin-4-yl)acrylate (1.8 g,7.09 mmol) in PhMe (40 mL), TsNHNH₂ (2.64 g, 14.2 mmol) and Et₃N (2.15g, 21.3 mmol) was added, the resulting mixture was heated to 100° C.overnight. The reaction was detected by TLC, TLC showed the appearanceof desired product, then, the solvent was removed under reducedpressure, H₂O was added and extracted with AcOEt (3×50 ml), the combinedorganic layers were washed by brine, dried over Na₂SO₄ and concentratedto get the crude product, which was purified by column chromatography onsilica gel (Petroleum Ether:EtOAc=3:2) to afford ethyl3-phenyl-3-(pyridazin-4-yl)propanoate (1.20 g, yield: 66%). ¹H NMR(CDCl₃ 400 MHz): δ9.12 (d, J=2.0 Hz, 1H), 9.09 (d, J=6.8 Hz, 1H),7.40-7.24 (m, 4H), 7.20 (d, J=7.2 Hz, 2H), 4.56 (t, J=8.0 Hz, 1H), 4.08(q, J=7.2 Hz, 2H), 3.09 (d, J=8.0 Hz, 2H), 1.15 (t, J=7.2 Hz, 3H).

3-Phenyl-3-(pyridazin-4-yl)propanoic acid

To a solution of ethyl 3-phenyl-3-(pyridazin-4-yl)propanoate (1.0 g, 3.9mmol) in MeOH (20 mL) was added 2N NaOH (6 mL, 11.7 mmol), the resultingmixture was stirred at room temperature overnight. MeOH was removedunder reduced pressure and pH adjusted to 4-5 by aq. HCl (2N), extractedwith AcOEt (6×100 ml), the combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated to get the3-phenyl-3-(pyridazin-4-yl)propanoic acid (750 mg, yield: 84%). ¹H NMR(CDCl₃ 400 MHz): δ9.27 (d, J=1.2 Hz, 1H), 9.09 (dd, J=4.0, 1.2 Hz, 1H),7.67 (dd, J=5.6, 2.4 Hz, 1H), 7.41-7.36 (m, 2H), 7.34-7.27 (m, 2H),7.24-7.18 (m, 1H), 4.48 (t, J=8.0 Hz, 1H), 3.27-3.15 (m, 1H), 3.10-3.00(m, 1H).

3-Phenyl-3-(pyridazin-4-yl)propanoyl azide

To a solution of 3-phenyl-3-(pyridazin-4-yl)propanoic acid (570 mg, 2.5mmol) in DMF (30 mL) was added Et₃N (505 mg, 5.0 mmol), followed by theDPPA (722 mg, 2.6 mmol) in portions at 0° C., the resulting mixture wasstirred at room temperature for 1.5 hour. The reaction was diluted withwater, extracted with AcOEt (3×40 ml), the combined organic layer waswashed by brine, dried over Na₂SO₄ and concentrated to get the3-phenyl-3-(pyridazin-4-yl)propanoyl azide (crude 650 mg), which wasused for next step directly.

tert-Butyl (2-phenyl-2-(pyridazin-4-yl)ethyl)carbamate

A solution of 3-phenyl-3-(pyridazin-4-yl)propanoyl azide (650 mg, 2.57mmol) in t-BuOH (3 ml) and PhMe (10 ml) was stirred at 80° C. overnight.The reaction was detected by LC-MS, LC-MS indicate the desired productwas formed, then, the solvent was removed under reduced pressure to getthe crude product, which was purified by column chromatography on silicagel (petroleum Ether:EtOAc=3:2˜1:2) to afford tert-butyl(2-phenyl-2-(pyridazin-4-yl)ethyl)carbamate (200 mg, yield: 26%). ¹H NMR(CDCl₃ 400 MHz): δ9.12-9.07 (m, 2H), 7.42-7.28 (m, 4H), 7.23-7.18 (m,2H), 4.62 (m, 1H), 4.30-4.20 (t, J=7.6 Hz, 1H), 3.95-3.83 (m, 1H),3.75-3.65 (m, 1H), 1.40 (s, 9H).

2-Phenyl-2-(pyridazin-4-yl)ethanamine

A solution of tert-butyl (2-phenyl-2-(pyridazin-4-yl)ethyl)carbamate(120 mg, 0.40 mmol) in DCM (2 ml) and TFA (2 ml) was stirred at roomtemperature for 4 hours. The solvent was removed under reduced pressureand the residue was diluted with sat.aq Na₂CO₃ to adjust pH=9-10, then,extracted with AcOEt (3×30 ml), the combined organic layer was washedwith brine, dried over Na₂SO₄ and concentrated to get the2-phenyl-2-(pyridazin-4-yl)ethanamine (crude 80 mg), which was used fornext step directly.

5-(Diisopropoxymethyl)-2-methylpyrimidine

To a mixture of 2-methylpyrimidine-5-carbaldehyde (1.0 g, 8.2 mmol) andtriisopropoxymethane (2.3 g, 12 mmol) in isopropanol (15 ml) was addedmethanesulfonic acid (0.079 g, 0.053 ml, 0.819 mmol). The reaction wasstirred at room temperature for 23 hours. Potassium carbonate (1.132 g,8.19 mmol) was added and the mixture was filtered and the solution wasconcentrated in vacuo. The crude mixture was purified by flashchromatography to yield 5-(diisopropoxymethyl)-2-methylpyrimidine (536mg, 29%)

¹H NMR (500 MHz, CDCl₃) δ 8.71 (s, 2H), 5.60 (s, 1H), 3.93 (dt, J=12.3,6.1 Hz, 2H), 2.74 (s, 3H), 1.21 (dd, J=14.8, 6.1 Hz, 12H).

2-Isopropoxy-2-(2-methylpyrimidin-5-yl)acetonitrile

A solution of 5-diisopropoxymethyl-2-methyl-pyrimidine (335 mg, 1.49mmol) in DCM (5 mL, 80 mmol) was cooled at 0° C. Zinc diiodide (47.7 mg,0.149 mmol) TMSCN (219 uL, 1.64 mmol) were added and cooling removed.After stirring for 24 hours TLC indicated that starting material waspresent. TMSCN (60 uL, 0.45 mmol) and zinc diiodide (48 mg, 0.15 mmol)were added and the reaction was stirred for a further 3.5 hours. Thereaction was poured into water (20 mL) and extracted with DCM (3×20 mL).The combined organic phases were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude product was purified by flashchromatography 2-Isopropoxy-2-(2-methylpyrimidin-5-yl)acetonitrile (217mg, 76%).

¹H NMR (500 MHz, CDCl₃) δ 8.75 (s, 2H), 5.29 (s, 1H), 4.21-3.95 (m, 1H),2.78 (s, 3H), 1.32 (dd, J=21.7, 6.1 Hz, 6H).

2-Isopropoxy-2-(2-methylpyrimidin-5-yl)ethanamine

2-Isopropoxy-2-(2-methylpyrimidin-5-yl)acetonitrile (169 mg, 0.884 mmol)was dissolved in methanol (10 ml) and 7M NH₃ in methanol (4 ml). Argonwas bubbled through the solution for 5 minutes. To the reaction wasadded Raney nickel (100 mg, 1.704 mmol) and it was fitted with aH₂-filled balloon. After stirring at room temperature for 20 hours LCMSshows only around 30% conversion and raney nickel (100 mg, 1.70 mmol)was added. The reaction was stirred for another 72 hours, then filteredthrough a plug of celite and concentrated in vacuo. The crude productused for next reaction without further purification.

LC-MS (m/z) 196.2 (MH⁺), t_(R) (minutes, Method D)=0.29.

The following intermediates were prepared in a similar way:

-   4-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)butan-1-amine;

(1-Methyl-1H-pyrazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanone

A solution of 4-iodo-1-methyl-1H-pyrazole (0.80 g, 3.9 mmol) in THF(7.04 g, 8.00 ml, 98 mmol) was cooled at 0° C. A solution ofisopropylmagnesium chloride lithium chloride complex in THF (5.42 ml,4.23 mmol, 0.78 molar) was added dropwise and the reaction was stirredfor 1½ hour. A solution ofN-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (0.733 g, 4.23 mmol)in THF (2 mL) was added dropwise. Cooling was removed after 15 min andreaction was then stirred for 2 hours. To the mixture was added 2 M HCl(20 mL) and it was extracted with AcOEt (3×25 mL). The combined organicphases were washed with brine, dried over MgSO₄ and concentrated invacuo. The crude product was purified by flash chromatography to yield(1-methyl-1H-pyrazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanone (220 mg,1.13 mmol, 29.4% yield).

¹H NMR (600 MHz, CDCl₃) δ 7.87 (s, 1H), 7.87 (s, 1H), 4.03 (ddd, J=11.4,4.1, 2.4 Hz, 2H), 3.92 (s, 3H), 3.49 (td, J=11.7, 2.3 Hz, 2H), 3.06 (tt,J=11.3, 3.8 Hz, 1H), 1.86 (dtd, J=13.8, 11.7, 4.4 Hz, 2H), 1.72 (ddd,J=13.4, 3.7, 2.0 Hz, 2H).

Ethyl 3-(1-methyl-1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)acrylate

Sodium hydride (60% suspension in mineral oil) (96 mg, 2.41 mmol, 60%)was suspended in THF (2 ml) under argon. Triethyl phosphonoacetate (492mg, 0.435 ml, 2.19 mmol) was added dropwise to the mixture over a periodof 30 min and the reaction was then stirred for 60 minutes.(1-Methyl-1H-pyrazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanone (213 mg,1.097 mmol) in THF (2.0 mL) was added dropwise. The reaction was stirredfor 3 hours at room temperature. Heated for 22 hours at reflux andcooled to room temperature. The reaction was poured into H₂O (25 mL) andextracted with AcOEt (3×25 mL), the combined organic phases were washedwith brine, dried over MgSO₄ and concentrated in vacuo. The crudeproduct was used for the next step without further purification.

Ethyl3-(1-methyl-1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate

Ethyl 3-(1-methyl-1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)acrylate(205 mg, 0.78 mmol) was dissolved in methanol (10 ml) and argon wasbubbled through the solution for 5 minutes. To the solution was added10% Pd/C (41 mg) and the flask was fitted with a balloon containinghydrogen. The reaction was stirred at room temperature for 16 hours. Thecatalyst was removed by filtration through a plug of celite. Andsolution was concentrated in vacuo. The crude product was used directlyin the next reaction.

tert-Butyl(2-(1-methyl-1H-pyrazol-4-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

Crudeethyl-3-(1-methyl-1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate(207 mg, 0.777 mmol) dissolved in THF (5 ml). Trimethylsilanol, sodiumsalt solution in THF (0.855 ml, 0.855 mmol, 1 molar) was added at roomtemperature. The mixture stirred for 3 days and concentrated in vacuo.LCMS showed only partial conversion. Trimethylsilanol, sodium saltsolution in THF (10 ml, 10.00 mmol, 1 molar) was added and mixturestirred overnight at room temperature. A 2 M HCl in solution in THF (20mL) was added to the reaction and it was stirred for 30 minutes. Themixture was now filtered through a plug of celite and concentrated invacuo. The crude carboxylic acid salt was suspended in tert-butanol (5ml). Triethyl amine (0.189 g, 0.260 ml, 1.865 mmol) anddiphenylphosphoryl azide (0.280 g, 0.219 ml, 1.017 mmol) were added andthe mixture was heated at 80° C. overnight. The reaction was cooled toroom temperature and poured into H₂O (15 mL) and extracted with AcOEt(3×15 mL). The combined organic phases were washed with brine, driedover MgSO4 and concentrated in vacuo. The crude product was purified byflash chromatography.

LC-MS (m/z) 310.2 (MH⁺), t_(R) (minutes, Method D)=0.62.

2-(1-Methyl-1H-pyrazol-4-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine

tert-Butyl(2-(1-methyl-1H-pyrazol-4-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(49 mg, 0.132 mmol) was dissolved in DCM (5 ml) and cooled at 0° C. TFA(740 mg, 0.5 ml, 6.49 mmol) was added and mixture stirred for 30 minafter which cooling was removed and the mixture was stirred for afurther 30 minutes.

Concentrated in vacuo to yield the crude amine as the trifluoroaceticacid salt.

5-(1,3-Dioxan-2-yl)-2-methylpyrimidine

To a solution of 2-methylpyrimidine-5-carbaldehyde (0.808 g, 6.62 mmol)and propane-1,3-diol (1.01 g, 0.868 ml, 13.2 mmol) in toluene (7.6 ml)and THF (1.9 ml) was added p-toluenesulfonic acid (11 mg, 0.066 mmol).The reaction was heated at 65° C. for 4.5 hours. The reaction mixturewas then poured into H₂O (50 mL) and extracted with AcOEt (3×50 mL). Thecombined organic phases were washed with brine, dried over MgSO₄ andconcentrated in vacuo to yield 5-(1,3-dioxan-2-yl)-2-methylpyrimidine(620 mg, 3.44 mmol, 52%) used for next step without furtherpurification.

2-(3-Hydroxypropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile

To an ice-cold solution of 5-(1,3-dioxan-2-yl)-2-methylpyrimidine (140mg, 0.78 mmol) in DCM (5.0 ml) was added zinc iodide (124 mg, 0.39mmol). Trimethylsilyl cyanide (116 mg, 0.155 ml, 1.17 mmol) was addeddropwise over a period of 10 minutes. Cooling was removed and thereaction was stirred for 40 hours at room temperature. The mixture waspoured into H₂O (20 mL) and extracted with DCM (3×20 mL), the combinedorg. phases were washed with brine, dried over MgSO₄ and concentrated invacuo. The crude product was used for next step without furtherpurification.

¹H NMR (600 MHz, CDCl₃) δ 8.78 (s, 2H), 5.32 (s, 1H), 4.00 (dt, J=8.9,6.0 Hz, 1H), 3.82 (dt, J=8.9, 6.1 Hz, 1H), 3.78 (t, J=6.0 Hz, 2H), 2.79(s, 3H), 1.95 (p, J=6.0 Hz, 2H).

2-(3-Bromopropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile

A solution of2-(3-hydroxypropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile (54 mg, 0.26mmol) and CBr₄ (259 mg, 0.782 mmol) in DCM (3 ml) was cooled at 0° C.Triphenylphosphine (205 mg, 0.782 mmol) in DCM (1 ml) was added dropwiseover a period of 5 minutes. The reaction was stirred for 2 hours andthen allowed to warm to room temperature. To the mixture was added Et₂O(5 mL) and the cloudy solution was filtered through a plug of celite.The resulting solution was concentrated in vacuo and purified by flashchromatography to yield2-(3-Bromopropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile.

¹H NMR (500 MHz, CDCl₃) δ 8.75 (s, 2H), 5.27 (s, 1H), 3.97 (m, 1H), 3.79(m, 1H), 3.47 (t, J=6.3 Hz, 2H), 2.77 (s, 3H), 2.24-2.12 (m, 2H).

2-(2-Methylpyrimidin-5-yl)tetrahydrofuran-2-carbonitrile

A solution of 2-(3-bromopropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile(24 mg, 0.089 mmol) in THF (3 mL) was cooled at −78° C. Lithiumbis(trimethylsilyl)amide in THF (141 μl, 0,141 mmol, 1 molar) was addedslowly and the mixture was stirred for 1 hour at −78° C. To the reactionmixture was added sat. aq. NH₄Cl (10 mL) and the mixture was allowed towarm to room temperature. The reaction mixture was diluted with H₂O (10mL) and extracted with AcOEt (3×15 mL). The combined org. phases werewashed with brine, dried over MgSO₄ and concentrated in vacuo. The crudeproduct was used directly for next step without further purification.

LC-MS (m/z) 190.1 (MH+), t_(R) (minutes, Method D)=0.38.

(2-(2-Methylpyrimidin-5-yl)tetrahydrofuran-2-yl)methanamine

2-(2-Methylpyrimidin-5-yl)tetrahydrofuran-2-carbonitrile (18 mg, 0.095mmol) was dissolved in MeOH (5 ml) and 7M NH₃ in MeOH (1 ml). Argon wasbubbled through the solution. Raney Nickel (6 mg, 0.1 mmol) was addedand the flask was fitted with a H₂-balloon and stirred at roomtemperature for 1½ hour. Reaction was filtered through a plug of celiteand concentrated in vacuo. Used for next step without furtherpurification.

LC-MS (m/z) 194.0 (MH+), t_(R) (minutes, Method D)=0.17.

(1-methyl-1H-pyrazol-4-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone

A solution of 5-bromo-2-(trifluoromethyl)pyridine (3.80 g, 16.82 mmol)in THF (24 ml) was cooled at −18° C. A solution of isopropylmagnesiumchloride lithium chloride complex in THF (17.97 ml, 14.02 mmol, 0.78molar) was added dropwise over a period of 30 minutes. The reaction wasthen cooled at −78° C. kept there for 1% hour. The reaction was allowedto reach −3° C. before being cooled to −10° C. A solution ofN-methoxy-N,1-dimethyl-1H-pyrazole-4-carboxamide (2.372 g, 14.02 mmol)in THF (8 ml) was added dropwise over a period of 5 minutes. Thereaction was allowed to warm to room temperature and stirred over night.Cooled to 0° C. and a 2 M HCl solution (150 mL) was added slowly. Thecrude mixture was extracted with AcOEt (3×150 mL), the combined org.phases were washed with brine, dried over MgSO₄ and concentrated invacuo. The crude product was purified by column chromatography to yield(1-methyl-1H-pyrazol-4-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone1.22 g (34%) as a light yellow solid.

¹H NMR (600 MHz, DMSO) δ 9.12 (d, J=2.0 Hz, 1H), 8.53 (s, 1H), 8.45(ddd, J=8.0, 2.1, 0.4 Hz, 1H), 8.10 (dd, J=8.1, 0.7 Hz, 1H), 8.06 (d,J=0.7 Hz, 1H), 3.93 (s, 3H).

LC-MS (m/z) 256.0 (MH+), t_(R) (minutes, Method D)=0.54.

Ethyl3-(1-methyl-1H-pyrazol-4-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate

Triethyl phosphonoacetate (2.1 g, 1.9 ml, 9.4 mmol) was added dropwiseto a suspension of sodium hydride suspension (0.41 g, 10.3 mmol, 60%) inTHF (10 ml). The mixture was stirred for 1½ hour and then a solution of(1-methyl-1H-pyrazol-4-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone(1.2 g, 4.7 mmol) in THF (10 ml) was added dropwise. The reaction wasstirred for 2 hours at room temperature and then heated at 65° C.overnight. The mixture was cooled to room temperature and poured intoH₂O (25 mL), extracted with EA (3×25 mL). The combined org. phaseswashed were washed with brine, dried over MgSO₄ and concentrated invacuo.

To the crude product was added MeOH (20 ml) and 10% Pd/C (0.500 g) andthe mixture was flushed with argon for 5 min and then fitted with aballoon containing H₂. After stirring at room temperature overnightcomplete conversion was observed by TLC. The reaction was filteredthrough celite, concentrated in vacuo and purified by flashchromatography to yield 1.15 g (75%) ethyl3-(1-methyl-1H-pyrazol-4-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate.

¹H NMR (600 MHz, DMSO) δ 8.75 (d, J=2.0 Hz, 1H), 8.01 (dd, J=8.1, 2.1Hz, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.57 (s, 1H), 7.37 (d, J=0.5 Hz, 1H),4.50 (t, J=8.0 Hz, 1H), 3.97 (qd, J=7.1, 0.9 Hz, 2H), 3.75 (s, 3H), 3.11(d, J=8.0 Hz, 2H), 1.05 (t, J=7.1 Hz, 3H).

LC-MS (m/z) 328.0 (MH+), t_(R) (minutes, Method E)=0.60.

tert-Butyl(2-(1-methyl-1H-pyrazol-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)carbamate

Ethyl3-(1-methyl-1H-pyrazol-4-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate(1.15 g, 3.51 mmol) was mixed with trimethylsilanol, sodium saltsolution in THF (30 ml, 30.0 mmol, 1 molar) and stirred for 24 hours atroom temperature. Trimethylsilanol, sodium salt solution in THF (30 ml,30.0 mmol, 1 molar) added and mixture stirred overnight at roomtemperature, LCMS shows incomplete conversion and reaction heated atreflux for 3 hours. The mixture was cooled on an ice bath and HCl inEt2O (48.0 g, 40 ml, 80 mmol, 2 molar) was added and after 10 min themixture was concentrated in vacuo. The crude reaction mixture was thensuspended dry THF (150 mL) and the solid filtered off. The liquid phasewas concentrated in vacuo and used for next step without purification.3-(1-methyl-1H-pyrazol-4-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoicacid (0.531 g, 1.774 mmol) dissolved in tert-butanol (10 ml. TEA (0.395g, 0.544 ml, 3.90 mmol) and diphenylphosphoryl azide (0.59 g, 0.46 ml,2.1 mmol) were added. Heated at 80° C. for 29 hours. The reaction waspoured into H₂O (50 mL) and extracted with EA (3×50 mL), the combinedorg. phases washed with brine, dried over MgSO₄, concentrated in vacuoand purified by flash chromatography to yield 49 mg (7%) tert-butyl(2-(1-methyl-1H-pyrazol-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)carbamate.

LC-MS (m/z) 371.2 (MH+), t_(R) (minutes, Method E)=0.67.

2-(1-Methyl-1H-pyrazol-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine

Tert-butyl(2-(1-methyl-1H-pyrazol-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)carbamate(49 mg, 0.132 mmol) was dissolved in DCM (5 ml) and cooled at 0° C. TFA(740 mg, 0.5 ml, 6.49 mmol) was added and mixture stirred for 30 minafter which cooling was removed and the mixture was stirred for afurther 30 minutes. Concentrated in vacuo to yield the crude amine asthe trifluoroacetic acid salt.

The following intermediates were prepared in a similar way:

-   2-(1-methyl-1H-pyrazol-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine;-   2-(1-methyl-1H-imidazol-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine;

C-(1-Methyl-4-phenyl-piperidin-4-yl)-methyl amine

Prepared according to the ref: Diamond, J. et al. J. Org. Chem., 1965,1840

C-(1-Pyridin-3-yl-cyclopentyl)-methylamine

Commercially available from Chengdu Chemicals

2-(4-Chloro-phenyl)-2-phenyl-ethylamine

Commercially available from Sigma Aldrich Chemicals

Compounds of formula I can be prepared by employing standard amide bondforming coupling procedures by the reaction of a carboxylic acid offormula II with an amine of formula III.

This reaction is typically carried out in a solvent such as THF or DMF,employing peptide coupling reagents exemplified by, but not limited toEDC and HOBt in the presence of a tertiary amine base such astriethylamine or diisopropylethylamine (DIPEA), at a temperature rangingfrom about 10° C. to about 30° C. Other non-limiting examples ofcoupling reagents include carbonyldiimidazole,N,N′-dicyclohexylcarbodiimide orbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate asreported by Coste et al. Tetrahedron Lett. (1990) 31 (2): 205. Or

Compounds of formula I can be prepared by employing standard amide bondforming coupling procedures by the reaction of a carboxylic acidchloride of formula IV with an amine of formula III.

This reaction is typically carried out in a solvent such as THF or DCMin the presence of a tertiary amine base such as triethylamine ordiisopropylethylamine (DIPEA), at a temperature ranging from about 10°C. to about 30° C.

Preparation of the Compounds of the Invention Example 1a2-Chloro-N-[4-(4-chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-2,3-dimethyl-benzamide

A mixture of [4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine(67.7 mg, 0.3 mmol), 2,3-dimethylbenzoyl chloride (53 mg, 0.315 mmol)and DIPEA (78 mg, 0.60 mmol) in DCM (1.5 mL) was stirred at roomtemperature for 16 h. The mixture was purified by preparative HPLC toyield the title compound (70.5 mg, yield: 66%). ¹H NMR (CDCl₃ 300 MHz):δ ppm 7.40-6.98 (m, 7H), 5.35 (bs, 1H), 3.95-3.87 (m, 2H), 3.70 (d, 2H),3.70-3.60 (m, 2H), 2.31 (s, 3H), 2.23 (s, 3H), 2.18-1.92 (m, 4H). LCMS(MH+): m/z=358.0, t_(R) (minutes, Method B)=1.03

The following compounds were synthesised in a similar way as to example1a:

Example 1bN-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-2-methoxy-benzamide

From 2-methoxybenzoyl chloride and[4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁺):m/z=360.0, t_(R) (minutes, Method B)=1.01

Example 1c2,3-Dichloro-N-[4-(4-chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-benzamide

From 2,3-dichlorobenzoyl chloride and[4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁺):m/z=399.9, t_(R) (minutes, Method B)=1.03

Example 1dN-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-2-methyl-benzamide

From 2-methylbenzoyl chloride and[4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁺):m/z=344.0, t_(R) (minutes, Method A)=1.26

Example 2a

2-Chloro-N-[4-(4-chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-5-methyl-benzamide

A mixture of [4-(4-Chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine(67.7 mg, 0.3 mmol), 2-chloro-5-methylbenzoic acid (54 mg, 0.315 mmol),PyBOP (187 mg, 0.36 mmol) and DIPEA (78 mg, 0.60 mmol) in DCM (1.5 mL)was stirred at room temperature for 16 h. The mixture was purified bypreparative HPLC to yield the title compound (35.5 mg, yield: 31%). LCMS(MH⁺): m/z=378.0, t_(R) (minutes, Method A)=1.38

The following compounds were synthesised in a similar way as to example2a:

Example 2bN-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-2-cyano-benzamide

From 2-cyanobenzoic acid and[4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁺):m/z=372.0, t_(R) (minutes, Method B)=0.96

Example 2c 2,3-Dichloro-N-(1-pyridin-3-yl-cyclopentylmethyl)-benzamide

From 2,3-dichlorobenzoic acid andC-(1-pyridin-3-yl-cyclopentyl)-methylamine. LCMS (MH⁺): m/z=348.9, t_(R)(minutes, Method A)=1.16

Example 2d 2,3-Dimethyl-N-(1-pyridin-3-yl-cyclopentylmethyl)-benzamide

From 2,3-dimethylbenzoic acid andC-(1-pyridin-3-yl-cyclopentyl)-methylamine. LCMS (MH⁺): m/z=309.1, t_(R)(minutes, Method A)=1.11

Example 2e2-Chloro-5-methyl-N-(1-pyridin-3-yl-cyclopentylmethyl)-benzamide

From 2-chloro-5-methylbenzoic acid andC-(1-pyridin-3-yl-cyclopentyl)-methylamine. LCMS (MH⁺): m/z=329.0, t_(R)(minutes, Method A)=1.14

Example 2fN-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-2-trifluoromethyl-benzamide

From 2-trifluoromethylbenzoic acid and[4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁺):m/z=397.9, t_(R) (minutes, Method B)=1.04

Example 2g 2-Methyl-N-(1-pyridin-3-yl-cyclopentylmethyl)-benzamide

From 2-methylbenzoic acid andC-(1-pyridin-3-yl-cyclopentyl)-methylamine. LCMS (MH⁺): m/z=357.0, t_(R)(minutes, Method B)=1.16

Example 2hN-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-2-fluoro-3-trifluoromethyl-benzamide

From 2-fluoro-3-trifluoromethylbenzoic acid and[4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁺):m/z=415.9, t_(R) (minutes, Method B)=1.19

Example 2i3-Chloro-N-[4-chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-2-fluoro-benzamide

From 3-chloro-2-fluorobenzoic acid and[4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁺):m/z=381.9, t_(R) (minutes, Method B)=1.10

Example 2jN-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-2,5-difluoro-benzamide

From 2,5-difluorobenzoic acid and[4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁺):m/z=366.0, t_(R) (minutes, Method B)=1.05

Example 2k2-Chloro-N-[1-(4-methoxy-phenyl)-cyclopentylmethyl]-5-methyl-benzamide

From 2-chloro-5-methylbenzoic acid and[1-(4-methoxyphenyl)-cyclopentyl]-methylamine. LCMS (MH⁺): m/z=358.0,t_(R) (minutes, Method B)=1.13

Example 212,3-Dichloro-N-[1-(4-methoxy-phenyl)-cyclopentylmethyl]-benzamide

From 2,3-dichlorobenzoic acid and[1-(4-methoxyphenyl)-cyclopentyl]-methylamine. LCMS (MH⁺): m/z=377.9,t_(R) (minutes, Method B)=1.22

Example 2m N-[1-(4-Methoxy-phenyl)-cyclopentylmethyl]-2-methyl-benzamide

From 2-methylbenzoic acid and[1-(4-methoxyphenyl)-cyclopentyl]-methylamine. LCMS (MH⁺): m/z=324.0,t_(R) (minutes, Method B)=1.18

Example 2nN-[1-(4-Methoxy-phenyl)-cyclopentylmethyl]-2,3-dimethyl-benzamide

From 2,3-dimethylbenzoic acid and[1-(4-methoxyphenyl)-cyclopentyl]-methylamine. LCMS (MH⁺): m/z=338.0,t_(R) (minutes, Method B)=1.23

Example 2o2,3-Dichloro-N-(1-methyl-4-phenyl-piperidin-4-ylmethyl)-benzamide

From 2,3-dichlorobenzoic acid andC-(1-methyl-4-phenyl-piperidin-4-yl)-methylamine. LCMS (MH⁺): m/z=376.9,t_(R) (minutes, Method A)=0.69

Example 2p2,3-Dimethyl-N-(1-methyl-4-phenyl-piperidin-4-ylmethyl)-benzamide

From 2,3-dimethylbenzoic acid andC-(1-methyl-4-phenyl-piperidin-4-yl)-methylamine. LCMS (MH⁺): m/z=337.0,t_(R) (minutes, Method A)=0.65

Example 2q2-Chloro-5-methyl-N-(1-methyl-4-phenyl-piperidin-4-ylmethyl)-benzamide

From 2-chloro-5-methylbenzoic acid andC-(1-methyl-4-phenyl-piperidin-4-yl)-methylamine. LCMS (MH⁺): m/z=367.0,t_(R) (minutes, Method A)=0.68

Example 2r 2-Methyl-N-(1-methyl-4-phenyl-piperidin-4-ylmethyl)-benzamide

From 2-methylbenzoic acid andC-(1-methyl-4-phenyl-piperidin-4-yl)-methylamine. LCMS (MH⁺): m/z=323.1,t_(R) (minutes, Method A)=0.56

Example 2sN-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-2,3,5-trifluoro-benzamide

From 2,3,5-trifluorobenzoic acid and[4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁺):m/z=384.0, t_(R) (minutes, Method B)=1.25

Example 2tN-[2-(4-Chloro-phenyl)-4-dimethylamino-butyl]-2-methyl-benzamide

From 2-methylbenzoic acid and3-(4-chloro-phenyl)-N1,N1-dimethyl-butane-1,4-diamine. LCMS (MH⁺):m/z=345.1, t_(R) (minutes, Method A)=0.8

Example 2u2-Chloro-N-[4-(4-chloro-phenyl)-1-methyl-piperidin-4-ylmethyl]-5-methyl-benzamide

From 2-chloro-5-methylbenzoic acid and[4-(4-chloro-phenyl)-1-methyl-piperidine-4-yl]-methylamine. LCMS (MH⁺):m/z=391.0, t_(R) (minutes, Method B)=0.71

Example 2vN-[4-(4-Chloro-phenyl)-1-methyl-piperidin-4-ylmethyl]-2-methyl-benzamide

From 2-methylbenzoic acid and[4-(4-chloro-phenyl)-1-methyl-piperidine-4-yl]-methylamine. LCMS (MH⁺):m/z=357.1, t_(R) (minutes, Method B)=0.61

Example 2w2,3-Dichloro-N-[4-methyl-2-(6-methyl-pyridin-3-yl)-pentyl]-benzamide

From 2,3-dichlorobenzoic acid and4-methyl-2-(6-methylpyridin-3-yl)-pentylamine. LCMS (MH⁺): m/z=364.9,t_(R) (minutes, Method A)=1.43

Example 2x2,3-Dimethyl-N-[4-methyl-2-(6-methyl-pyridin-3-yl)-pentyl]-benzamide

From 2,3-dimethylbenzoic acid and4-methyl-2-(6-methylpyridin-3-yl)-pentylamine. LCMS (MH⁺): m/z=325.0,t_(R) (minutes, Method A)=1.38

Example 2y2-Methyl-N-[4-methyl-2-(6-methyl-pyridin-3-yl)-pentyl]-benzamide

From 2-methylbenzoic acid and4-methyl-2-(6-methylpyridin-3-yl)-pentylamine. LCMS (MH⁺): m/z=311.0,t_(R) (minutes, Method A)=1.31

Example 2z2-Chloro-5-methyl-N-[4-(6-methyl-pyridin-3-yl)-tetrahydro-pyran-4-ylmethyl]-benzamide

From 2-chloro-5-methylbenzoic acid andC-[4-(6-methylpyridin-3-yl)-tetrahydropyran-4-yl]methylamine. LCMS(MH⁺): m/z=359.0, t_(R) (minutes, Method B)=0.74

Example 2a12-Methyl-N-[4-(6-methyl-pyridin-3-yl)-tetrahydro-pyran-4-ylmethyl]-benzamide

From 2-methylbenzoic acid andC-[4-(6-methylpyridin-3-yl)-tetrahydropyran-4-yl]methylamine. LCMS(MH⁺): m/z=325.0, t_(R) (minutes, Method B)=0.60

Example 2b15-Bromo-2-chloro-N-[4-(4-chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-benzamide

From 5-bromo-2-chlorobenzoic acid and[4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁺):m/z=443.7, t_(R) (minutes, Method A)=1.52

Example 2c12-Chloro-N-[4-(4-chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-benzamide

From 2-chlorobenzoic acid and[4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁺):m/z=363.9, t_(R) (minutes, Method A)=1.34

Example 3a2,3-Dichloro-N-[[4,4-difluoro-1-(6-fluoro-3-pyridyl)cyclohexyl]methyl]benzamide

A solution ofC-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine (38mg, 0.157 mmol), 2,3-dichlorobenzoic acid (30 mg, 0.157 mmol), HOBt (25mg, 0.185 mmol), EDCI.HCl (36 mg, 0.185 mmol) and DIPEA (48 mg, 0.345mmol) in DMF (2 mL) was stirred at room temperature overnight. Water wasadded to the solution followed by extraction with EtOAc (3×10 ml). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by Prep. HPLC to give thetitle compound (25 mg, yield: 38%). ¹H NMR (CDCl₃ 300 MHz): δ ppm 8.18(d, J=2.8 Hz, 1H), 7.89-7.80 (m, 1H), 7.50 (dd, J=8.0 Hz, 2.0 Hz, 1H),7.33 (dd, J=7.6 Hz, 1.6 Hz, 1H), 7.28-7.18 (m, 1H), 6.98 (dd, J=8.8 Hz,3.2 Hz, 1H), 5.85 (t, J=6.8 Hz, 1H), 3.64 (d, J=6.8 Hz, 2H), 2.36-2.00(m, 6H), 1.87-1.65 (m, 2H). LCMS (MH⁺): m/z=417.1, t_(R) (minutes,Method C)=1.11

The following compounds were synthesised in a similar way as to example3a, purification of the compounds was performed by prep. HPLC orCombiflash:

Example 3b2-Chloro-N-[[4,4-difluoro-1-(6-fluoro-3-pyridyl)cyclohexyl]methyl]-6-fluoro-benzamide

From 2-chloro-6-fluorobenzoic acid andC-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH⁺): m/z=401.1, t_(R) (minutes, Method C)=1.07

Example 3c2-Chloro-N-[[4,4-difluoro-1-(6-fluoro-3-pyridyl)cyclohexyl]methyl]-5-methyl-benzamide

From 2-chloro-5-methylbenzoic acid andC-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH⁺): m/z=397.2, t_(R) (minutes, Method C)=1.11

Example 3d2-Chloro-N-[[4,4-difluoro-1-(6-fluoro-3-pyridyl)cyclohexyl]methyl]-5-(trifluoromethyl)benzamide

From 2-chloro-5-trifluoromethylbenzoic acid andC-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH⁺): m/z=451.1, t_(R) (minutes, Method C)=1.15

Example 3eN-[4,4-Difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-2-fluoro-benzamide

From 2-fluorobenzoic acid andC-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH⁺): m/z=367.1, t_(R) (minutes, Method D)=0.69

Example 3f4-Cyano-N-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-2-fluoro-benzamide

From 2-fluoro-4-cyanobenzoic acid andC-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH⁺): m/z=392.1, t_(R) (minutes, Method D)=0.68

Example 3gN-[4,4-Difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-2-fluoro-3-methoxy-benzamide

From 2-fluoro-3-methoxybenzoic acid andC-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH⁺): m/z=397.2, t_(R) (minutes, Method D)=0.69

Example 3h2-Chloro-N-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-5-methanesulfonyl-benzamide

From 2-chloro-5-methanesulfonylbenzoic acid andC-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH⁺): m/z=461.1, t_(R) (minutes, Method D)=0.64

Example 3i2-Chloro-N-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-benzamide

From 2-chlorobenzoic acid andC-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH⁺): m/z=383.1, t_(R) (minutes, Method D)=0.69

Example 3jN-[4,4-Difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-2-fluoro-5-methoxy-benzamide

From 2-fluoro-5-methoxybenzoic acid andC-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH⁺): m/z=397.1, t_(R) (minutes, Method D)=0.71

Example 3kN-[4,4-Difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-2-fluoro-3-methyl-benzamide

From 2-fluoro-3-methylbenzoic acid andC-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH⁺): m/z=381.1, t_(R) (minutes, Method D)=0.74

Example 31N-[4,4-Difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-2,5-difluoro-benzamide

From 2,5-difluorobenzoic acid andC-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH⁺): m/z=385.2, t_(R) (minutes, Method D)=0.71

Example 3m2,5-Dichloro-N-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-benzamide

From 2,5-dichlorobenzoic acid andC-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH⁺): m/z=417.1, t_(R) (minutes, Method D)=0.76

Example 3n2-Chloro-N-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-5-methoxy-benzamide

From 2-chloro-5-methoxybenzoic acid andC-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH⁺): m/z=413.1, t_(R) (minutes, Method D)=0.72

Example 30N-[4,4-Difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-2,3-difluoro-benzamide

From 2,3-difluorobenzoic acid andC-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH⁺): m/z=385.0, t_(R) (minutes, Method D)=0.71

Example 3p2,3-Dichloro-N-[4-(4-chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-benzamide

From 2,3-dichlorobenzoic acid and[4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁺):m/z=398.1, t_(R) (minutes, Method D)=0.79

Example 3q2,3-Dichloro-N-[4-(4-trifluoromethyl-phenyl)-tetrahydro-pyran-4-ylmethyl]-benzamide

From 2,3-dichlorobenzoic acid and[4-(4-trifluoromethyl-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS(MH⁺): m/z=432.0, t_(R) (minutes, Method E)=0.83

Example 3r2,3-Dichloro-N-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-benzamide

From 2,3-dichlorobenzoic acid andC-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine.LCMS (MH⁺): m/z=467.0, t_(R) (minutes, Method E)=0.83

Example 3s2,3-Dichloro-N-[4-(6-trifluoromethyl-pyridin-3-yl)-tetrahydro-pyran-4-ylmethyl]-benzamide

From 2,3-dichlorobenzoic acid and[4-(6-trifluoromethyl-pyridin-3-yl)-tetrahydro-pyran-4-yl]-methylamine.LCMS (MH⁺): m/z=433.3, t_(R) (minutes, Method E)=0.72

Example 3t2,3-Dichloro-N-[1-(6-cyclopropyl-pyridin-3-yl)-4,4-difluoro-cyclohexylmethyl]-benzamide

From 2,3-dichlorobenzoic acid andC-[4,4-difluoro-1-(6-cyclopropyl-pyridin-3-yl)-cyclohexyl]-methylamine.LCMS (MH⁺): m/z=439.0, t_(R) (minutes, Method E)=0.55

Example 3u2,3-Dichloro-N-[4,4-difluoro-1-(6-methoxy-pyridin-3-yl)-cyclohexylmethyl]-benzamide

From 2,3-dichlorobenzoic acid andC-[4,4-difluoro-1-(6-methoxy-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH⁺): m/z=429.1, t_(R) (minutes, Method D)=0.67

Example 3v2-Cyano-N-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-benzamide

From 2-cyanobenzoic acid andC-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine.LCMS (MH⁺): m/z=424.2, t_(R) (minutes, Method D)=0.66

Example 3w2-Chloro-N-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-4-methanesulfonyl-benzamide

From 2-chloro-4-methanesulfonylbenzoic acid andC-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine.LCMS (MH⁺): m/z=511.1, t_(R) (minutes, Method D)=0.68

Example 3xN-[4,4-Difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-2-methyl-benzamide

From 2-methylbenzoic acid andC-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine.LCMS (MH⁺): m/z=413.2, t_(R) (minutes, Method D)=0.74

Example 3y2,3-Dichloro-N-[2-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-benzamide

From 2,3-dichlorobenzoic acid and2-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine. LCMS (MH⁺):m/z=403.1, t_(R) (minutes, Method D)=0.79

Example 3zN-[4,4-Difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-2-methanesulfonyl-benzamide

From 2-methaneulfonylbenzoic acid andC-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine.LCMS (MH⁺): m/z=413.2, t_(R) (minutes, Method D)=0.74

Example 3a12,3-Dichloro-N-[4,4-difluoro-1-(5-fluoro-pyridin-3-yl)-cyclohexylmethyl]-benzamide

From 2,3-dichlorobenzoic acid andC-[4,4-difluoro-1-(5-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS(MH+): m/z=417.2, t_(R) (minutes, Method D)=0.68

Example 3b12,3-Dichloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

From 2,3-dichlorobenzoic acid and3-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine. LCMS(MH+): m/z=416.9, t_(R) (minutes, Method C)=1.29

Example 3c12-Chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

From 2-chlorobenzoic acid and3-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine. LCMS(MH+): m/z=382.9, t_(R) (minutes, Method C)=1.24

Example 3d1N-[4,4-Difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-3-fluoro-2-methyl-benzamide

From 3-fluoro-2-methylbenzoic acid andC-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine.LCMS (MH+): m/z=431.2, t_(R) (minutes, Method D)=0.79

Example 3e1N-[4,4-Difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-3-methoxy-2-methyl-benzamide

From 3-methoxy-2-methylbenzoic acid andC-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine.LCMS (MH+): m/z=443.2, t_(R) (minutes, Method D)=0.78

Example 3f1N-[4,4-Difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-5-fluoro-2-methyl-benzamide

From 5-fluoro-2-methylbenzoic acid andC-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine.LCMS (MH+): m/z=431.2, t_(R) (minutes, Method D)=0.79

Example 3g1N-[4,4-Difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-2-methyl-5-trifluoromethyl-benzamide

From 5-trifluoromethyl-2-methylbenzoic acid andC-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine.LCMS (MH+): m/z=481.1, t_(R) (minutes, Method D)=0.86

Example 3h13-Bromo-N-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-2-methyl-benzamide

From 3-bromo-2-methylbenzoic acid andC-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine.LCMS (MH+): m/z=491.1, t_(R) (minutes, Method D)=0.84

Example 3i12-Chloro-N-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-3-methyl-benzamide

From 2-chloro-3-methylbenzoic acid andC-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine.LCMS (MH+): m/z=447.1, t_(R) (minutes, Method D)=0.80

Example 3j13-Cyano-N-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-2-methyl-benzamide

From 3-cyano-2-methylbenzoic acid andC-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine.LCMS (MH+): m/z=438.2, t_(R) (minutes, Method D)=0.75

Example 3k12,3-Dichloro-N-[2-(5-chloro-pyridin-3-yl)-3-cyclopropyl-propyl]-benzamide

From 2,3-dichlorobenzoic acid and3-cyclopropyl-2-(5-chloro-pyridin-3-yl)-propylamine. LCMS (MH+):m/z=383.0, t_(R) (minutes, Method D)=0.74

Example 3l12,3-Dichloro-N-[2-(4-chloro-phenyl)-2-phenyl-ethyl]-benzamide

From 2,3-dichlorobenzoic acid and2-(4-chloro-phenyl)-2-phenyl-ethylamine. LCMS (MH+): m/z=404.0, t_(R)(minutes, Method D)=0.91

Example 3m12,3-Dichloro-N-[3-cyclopropyl-2-(2,6-dimethyl-3-pyridyl)propyl]benzamide

From 2,3-dichlorobenzoic acid and3-cyclopropyl-2-(2,6-dimethyl-pyridin-3-yl)-propylamine. LCMS (MH+):m/z=377.1, t_(R) (minutes, Method G)=1.68

Example 3n12,3-Dichloro-N-[2-(2-methylpyrimidin-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propyl]benzamide

From 2,3-dichlorobenzoic acid and2-(2-methyl-pyrimidin-5-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine.LCMS (MH+): m/z=377.1, t_(R) (minutes, Method F)=1.68

Example 3o12,3-Dichloro-N-[3-[1-(trifluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

From 2,3-dichlorobenzoic acid and3-(1-trifluoromethyl-cyclopropyl)-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine.LCMS (MH+): m/z=485.1, t_(R) (minutes, Method G)=2.74

Example 3p12,3-Dichloro-N-[2-(6-cyclopropyl-3-pyridyl)-3-[1-(trifluoromethyl)cyclopropyl]propyl]benzamide

From 2,3-dichlorobenzoic acid and2-(6-cyclopropyl-pyridin-3-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine.LCMS (MH+): m/z=457.1, t_(R) (minutes, Method G)=1.96

Example 3q12,3-Dichloro-N-[2-(6-cyclopropyl-3-pyridyl)-3-[1-(difluoromethyl)cyclopropyl]propyl]benzamide

From 2,3-dichlorobenzoic acid and2-(6-cyclopropyl-pyridin-3-yl)-3-(1-difluoromethyl-cyclopropyl)-propylamine.LCMS (MH+): m/z=439.1, t_(R) (minutes, Method G)=2.09

Example 3r12,3-Dichloro-N-[3-[1-(difluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

From 2,3-dichlorobenzoic acid and2-(6-trifluoromethyl-pyridin-3-yl)-3-(1-difluoromethyl-cyclopropyl)-propylamine.LCMS (MH+): m/z=467.1, t_(R) (minutes, Method G)=2.62

Example 3s12-Chloro-N-[2-(6-cyclopropyl-3-pyridyl)-3-[1-(trifluoromethyl)cyclopropyl]propyl]benzamide

From 2-chlorobenzoic acid and2-(6-cyclopropyl-pyridin-3-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine.LCMS (MH+): m/z=423.1, t_(R) (minutes, Method G)=2.04

Example 3t1N-[2-(6-Cyclopropyl-3-pyridyl)-3-[1-(trifluoromethyl)cyclopropyl]propyl]-2-fluoro-benzamide

From 2-fluorobenzoic acid and2-(6-cyclopropyl-pyridin-3-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine.LCMS (MH+): m/z=407.1, t_(R) (minutes, Method G)=2.01

Example 3u12-Chloro-N-[3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl]benzamide

From 2-chlorobenzoic acid and2-(2-methyl-pyrimidin-5-yl)-3-cyclopropyl-propylamine. LCMS (MH+):m/z=330.1, t_(R) (minutes, Method F)=2.32

Example 3v12,3-Dichloro-N-[3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl]benzamide

From 2,3-dichlorobenzoic acid and2-(2-methyl-pyrimidin-5-yl)-3-cyclopropyl-propylamine. LCMS (MH+):m/z=364.1, t_(R) (minutes, Method F)=2.52

Example 3w12-Chloro-N-[3-[1-(trifluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

From 2-chlorobenzoic acid and3-(1-trifluoromethyl-cyclopropyl)-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine.LCMS (MH+): m/z=451.1, t_(R) (minutes, Method G)=2.58

Example 3x12-Fluoro-N-[3-[1-(trifluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

From 2-fluorobenzoic acid and3-(1-trifluoromethyl-cyclopropyl)-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine.LCMS (MH+): m/z=435.1, t_(R) (minutes, Method G)=2.58

Example 3y12-Chloro-N-[[4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl]methyl]benzamide

From 2-chlorobenzoic acid andC-[4,4-difluoro-1-(2-methyl-pyrimidin-5-yl)-cyclohexyl]-methylamine.LCMS (MH+): m/z=380.1, t_(R) (minutes, Method F)=2.37

Example 3z12,3-Dichloro-N-[[4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl]methyl]benzamide

From 2,3-dichlorobenzoic acid andC-[4,4-difluoro-1-(2-methyl-pyrimidin-5-yl)-cyclohexyl]-methylamine.LCMS (MH+): m/z=414.1, t_(R) (minutes, Method F)=2.57

Example 3a22,3-Dichloro-N-[3-cyclopropyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide

From 2,3-dichlorobenzoic acid and2-(2-trifluoromethyl-pyrimidin-5-yl)-3-cyclopropyl-propylamine. LCMS(MH+): m/z=418.1, t_(R) (minutes, Method G)=2.55

Example 3b22,3-Dichloro-N-[[4,4-difluoro-1-[6-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]cyclohexyl]methyl]benzamide

From 2,3-dichlorobenzoic acid and2-[5-(1-aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-propan-2-ol.LCMS (MH+): m/z=457.1, t_(R) (minutes, Method F)=1.97

Example 3c22-Chloro-N-[[4,4-difluoro-1-[6-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]cyclohexyl]methyl]benzamide

From 2-chlorobenzoic acid and2-[5-(1-aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-propan-2-ol.LCMS (MH+): m/z=423.2, t_(R) (minutes, Method F)=1.78

Example 3d22-chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]-3-methoxy-benzamide

From 2-chloro-3-methoxybenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS(MH+): m/z=413.1, t_(R) (minutes, Method G)=2.84

Example 3e22-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-6-fluorobenzamide

From 2-chloro-6-fluorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS(MH+): m/z=401.1, t_(R) (minutes, Method G)=2.88

Example 312N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-methoxybenzamide

From 2-methoxybenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS(MH+): m/z=379.1, t_(R) (minutes, Method G)=2.91

Example 3g2N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2,6-difluorobenzamide

From 2,6-difluorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS(MH+): m/z=385.1, t_(R) (minutes, Method G)=2.82

Example 3h22-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-5-(methylsulfonyl)benzamide

From 2-chloro-5-(methylsulfonyl)benzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS(MH+): m/z=461.1, t_(R) (minutes, Method G)=2.88

Example 3i22-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-3-fluorobenzamide

From 2-chloro-3-fluorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS(MH+): m/z=401.1, t_(R) (minutes, Method G)=2.51

Example 3j22-chloro-N-(3-cyclopropyl-2-(6-fluoropyridin-3-yl)propyl)benzamide

From 2-chlorobenzoic acid and3-cyclopropyl-2-(6-fluoropyridin-3-yl)propan-1-amine. LCMS (MH+):m/z=333.1, t_(R) (minutes, Method F)=2.43

Example 3k22,3-dichloro-N-(3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propan-1-amine. LCMS (MH+):m/z=364.1, t_(R) (minutes, Method F)=2.52

Example 3l22-chloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2-chlorobenzoic acid and3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine.

LCMS (MH+): m/z=398.1, t_(R) (minutes, Method F)=2.64

Example 3m22-chloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3-fluorobenzamide

From 2-chloro-3-fluorobenzoic acid and3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine.

LCMS (MH+): m/z=416.1, t_(R) (minutes, Method G)=2.49

Example 3n22,3-dichloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS(MH+): m/z=418.1, t_(R) (minutes, Method G)=2.48

Example 3o22-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2-chlorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS(MH+): m/z=384.1, t_(R) (minutes, Method F)=2.55

Example 3p22-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3-fluorobenzamide

From 2-chloro-3-fluorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS(MH+): m/z=402.1, t_(R) (minutes, Method F)=2.61

Example 3q22-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-6-fluorobenzamide

From 2-chloro-6-fluorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS(MH+): m/z=402.1, t_(R) (minutes, Method F)=2.59

Example 3h22,3-dichloro-N-(2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+):m/z=412.1, t_(R) (minutes, Method G)=2.49

Example 3i22-chloro-N-(2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+):m/z=378.1, t_(R) (minutes, Method G)=2.34

Example 3i22-chloro-6-fluoro-N-(2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+):m/z=396.1, t_(R) (minutes, Method G)=2.36

Example 3i22-chloro-3-fluoro-N-(2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+):m/z=396.1, t_(R) (minutes, Method G)=2.36

Example 3j22,3-dichloro-N-((4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

From 2,3-dichlorobenzoic acid and(4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS(MH+): m/z=380.1, t_(R) (minutes, Method F)=1.80

Example 3k22-chloro-N-((4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

From 2-chlorobenzoic acid and(4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS(MH+): m/z=346.1, t_(R) (minutes, Method F)=1.55

Example 3i22-chloro-6-fluoro-N-((4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

From 2-chloro-6-fluorobenzoic acid and(4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS(MH+): m/z=364.1, t_(R) (minutes, Method F)=1.57

Example 3m22-chloro-3-fluoro-N-((4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

From 2-chloro-3-fluorobenzoic acid and(4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS(MH+): m/z=364.1, t_(R) (minutes, Method F)=1.95

Example 3n22,3-dichloro-N-((4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

From 2,3-dichlorobenzoic acid and(4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine.LCMS (MH+): m/z=434.1, t_(R) (minutes, Method F)=2.34

Example 3o22-chloro-N-((4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

From 2-chlorobenzoic acid and(4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine.LCMS (MH⁺): m/z=400.1, t_(R) (minutes, Method F)=2.15

Example 3p22-chloro-6-fluoro-N-((4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

From 2-chloro-6-fluorobenzoic acid and(4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine.LCMS (MH+): m/z=418.1, t_(R) (minutes, Method F)=2.17

Example 3q22-chloro-3-fluoro-N-((4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

From 2-chloro-3-fluorobenzoic acid and(4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine.LCMS (MH+): m/z=418.1, t_(R) (minutes, Method F)=2.24

Example 3q22,3-dichloro-N-(3-cyclopropyl-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and2-(5-(1-amino-3-cyclopropylpropan-2-yl)pyridin-2-yl)propan-2-ol. LCMS(MH+): m/z=407.1, t_(R) (minutes, Method F)=1.98

Example 3r22-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3-methoxybenzamide

From 2-chloro-3-methoxybenzoic acid and3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS(MH+): m/z=414.0, t_(R) (minutes, Method F)=2.53

Example 3s22-methyl-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3-methoxybenzamide

From 2-methyl-3-methoxybenzoic acid and3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS(MH+): m/z=394.0, t_(R) (minutes, Method F)=2.59

Example 3t22,3-dichloro-N-(3-(1-fluorocyclopropyl)-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and3-(1-fluorocyclopropyl)-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine.LCMS (MH+): m/z=435.1, t_(R) (minutes, Method G)=2.46

Example 3u22,6-dichloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2,6-dichlorobenzoic acid and3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS(MH+): m/z=418.1, t_(R) (minutes, Method G)=2.62

Example 3v22,6-dichloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyridin-5-yl)propyl)benzamide

From 2,6-dichlorobenzoic acid and3-cyclopropyl-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine. LCMS(MH+): m/z=417.1, t_(R) (minutes, Method F)=2.50

Example 3x22,6-dichloro-N-(3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl)benzamide

From 2,6-dichlorobenzoic acid and3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propan-1-amine. LCMS (MH+):m/z=364.1, t_(R) (minutes, Method G)=2.43

Example 3y22,3-dichloro-N-(3-(1-fluorocyclopropyl)-2-(6-(trifluoromethyl)pyrimidin-3-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and3-(1-fluorocyclopropyl)-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine.LCMS (MH+): m/z=436.1, t_(R) (minutes, Method G)=2.61

Example 3z22,3-dichloro-N-((4,4-difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)benzamide

From 2,3-dichlorobenzoic acid and(4,4-difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl)methanamine.LCMS (MH+): m/z=468.1, t_(R) (minutes, Method G)=2.48

Example 3a32,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamine. LCMS (MH+):m/z=387.1, t_(R) (minutes, Method F)=1.56

Example 3b32-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamine. LCMS (MH+):m/z=353.1, t_(R) (minutes, Method F)=1.62

Example 3c32-chloro-6-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamine. LCMS (MH+):m/z=371.1, t_(R) (minutes, Method F)=1.65

Example 3d32-chloro-3-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamine. LCMS (MH+):m/z=371.1, t_(R) (minutes, Method F)=1.73

Example 3e32-chloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2-chlorobenzoic acid and3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine.LCMS (MH+): m/z=398.1, t_(R) (minutes, Method F)=2.62

Example 3i32-chloro-3-fluoro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2-chloro-3-fluorobenzoic acid and3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine.LCMS (MH+): m/z=416.1, t_(R) (minutes, Method G)=2.48

Example 3g32,3-dichloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine.LCMS (MH+): m/z=432.1, t_(R) (minutes, Method G)=2.58

Example 3h32-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS(MH+): m/z=360.1, t_(R) (minutes, Method F)=1.97

Example 3i32,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS(MH+): m/z=394.1, t_(R) (minutes, Method F)=1.88

Example 3j32-chloro-3-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS(MH+): m/z=378.1, t_(R) (minutes, Method F)=2.00

Example 3k32-chloro-6-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS(MH+): m/z=378.1, t_(R) (minutes, Method F)=2.06

Example 3i32,3-dichloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=428.1, t_(R) (minutes, Method G)=2.04

Example 3m32-chloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=394.1, t_(R) (minutes, Method F)=2.1

Example 3n32-chloro-6-fluoroN-(2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=412.1, t_(R) (minutes, Method F)=2.14

Example 3o32-chloro-3-fluoro-N-(2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=412.1, t_(R) (minutes, Method F)=2.18

Example 3p32-chloro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2-chlorobenzoic acid and3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(frifluoromethyl)pyrimidin-5-yl)propan-1-amine.LCMS (MH+): m/z=452.0, t_(R) (minutes, Method F)=3.03

Example 3q32,3-dichloro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine.LCMS (MH+): m/z=486.1, t_(R) (minutes, Method F)=2.77

Example 3r32-chloro-3-fluoro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2-chloro-3-fluorobenzoic acid and3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine.LCMS (MH+): m/z=470.0, t_(R) (minutes, Method F)=3.07

Example 3s32-chloro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propyl)benzamide

From 2-chlorobenzoic acid and3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine.LCMS (MH+): m/z=451.1, t_(R) (minutes, Method G)=2.50

Example 3t32,3-dichloro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine.LCMS (MH+): m/z=485.1, t_(R) (minutes, Method G)=2.63

Example 3u32-chloro-3-fluoro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propyl)benzamide

From 2-chloro-3-fluorobenzoic acid and3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine.LCMS (MH+): m/z=469.1, t_(R) (minutes, Method G)=2.54

Example 3v32,3-dichloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=448.0, t_(R) (minutes, Method F)=2.72

Example 3x32-chloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(tetrahydro-2H-pyran-4-yl)-2-(2-(tifluoromethyl)pyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=414.1, t_(R) (minutes, Method F)=2.54

Example 3y32-chloro-3-fluoro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=432.1, t_(R) (minutes, Method F)=2.48

Example 3z32-chloro-6-fluoro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=432.1, t_(R) (minutes, Method F)=2.6

Example 3a42,3-dichloro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS(MH+): m/z=457.0, t_(R) (minutes, Method G)=3.02

Example 3b42-chloro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS(MH+): m/z=423.1, t_(R) (minutes, Method G)=2.58

Example 3c42-chloro-3-fluoro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS(MH+): m/z=441.1, t_(R) (minutes, Method G)=2.63

Example 3d42-chloro-6-fluoro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS(MH+): m/z=441.0, t_(R) (minutes, Method G)=2.86

Example 3e42-chloro-N-(2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=407.1, t_(R) (minutes, Method F)=2.25

Example 3f42,3-dichloro-N-(2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=441.1, t_(R) (minutes, Method F)=2.43

Example 3g42-chloro-N-(2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethanamine. LCMS(MH+): m/z=406.1, t_(R) (minutes, Method F)=2.27

Example 3h42,3-dichloro-N-(2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethanamine. LCMS(MH+): m/z=440.0, t_(R) (minutes, Method F)=2.43

Example 3i42,3-dichloro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=458.0, t_(R) (minutes, Method G)=2.91

Example 3j42-chloro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=424.1, t_(R) (minutes, Method F)=3.19

Example 3k42-chloro-3-fluoro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=442.1, t_(R) (minutes, Method F)=3.24

Example 3i42-chloro-6-fluoro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=442.0, t_(R) (minutes, Method F)=2.99

Example 3m42-chloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=448.1, t_(R) (minutes, Method F)=2.95

Example 3n42,3-dichloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=482.1, t_(R) (minutes, Method G)=2.76

Example 3o42-chloro-6-fluoro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=466.1, t_(R) (minutes, Method F)=2.97

Example 3p42-chloro-3-fluoro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=466.1, t_(R) (minutes, Method F)=2.67

Example 3q42,3-dichloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS(MH+): m/z=448.1, t_(R) (minutes, Method F)=2.95

Example 3r42,3-dichloro-N-(4-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)butyl)benzamide

From 2,3-dichlorobenzoic acid and4-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)butan-1-amine. LCMS(MH+): m/z=422.0, t_(R) (minutes, Method F)=2.73

Example 3s4 2,3-dichloro-N-(2-phenyl-2-(pyridazin-4-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-phenyl-2-(pyridazin-4-yl)ethanamine.LCMS (MH+): m/z=372.1, t_(R) (minutes, Method G)=2.05

Example 3t4 2,4-dichloro-N-(2-phenyl-2-(pyridazin-4-yl)ethyl)benzamide

From 2,4-dichlorobenzoic acid and 2-phenyl-2-(pyridazin-4-yl)ethanamine.LCMS (MH+): m/z=372.1, t_(R) (minutes, Method G)=2.09

Example 3u42-chloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

From 2-chlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine. LCMS(MH+): m/z=365.1, t_(R) (minutes, Method F)=2.97

Example 3v42,3-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine. LCMS(MH+): m/z=399.1, t_(R) (minutes, Method G)=2.57

Example 3w42-chloro-3-fluoro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

From 2-chloro-3-fluorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine. LCMS(MH+): m/z=383.1, t_(R) (minutes, Method F)=3.02

Example 3x42-chloro-3-methoxy-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

From 2-chloro-3-methoxybenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine. LCMS(MH+): m/z=395.1, t_(R) (minutes, Method F)=2.96

Example 3y42,4-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

From 2,4-dichlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine. LCMS(MH+): m/z=399.1, t_(R) (minutes, Method G)=2.61

Example 3z42,6-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

From 2,6-dichlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine. LCMS(MH+): m/z=399.1, t_(R) (minutes, Method F)=3.06

Example 3a52-chloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2-chlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS(MH+): m/z=366.1, t_(R) (minutes, Method F)=2.84

Example 3b52,3-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS(MH+): m/z=400.1, t_(R) (minutes, Method F)=3.00

Example 3c52-chloro-3-fluoro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2-chloro-3-fluorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS(MH+): m/z=384.1, t_(R) (minutes, Method F)=2.90

Example 3d52-chloro-3-methoxy-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2-chloro-3-methoxybenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS(MH+): m/z=396.1, t_(R) (minutes, Method F)=2.84

Example 3e52,4-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2,4-dichlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS(MH+): m/z=400.1, t_(R) (minutes, Method F)=3.04

Example 3f52,6-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2,6-dichlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS(MH+): m/z=400.1, t_(R) (minutes, Method F)=2.93

Example 3g52,3-dichloro-N-((4,4-difluoro-1-(4-methyl-1H-imidazol-1-yl)cyclohexyl)methyl)benzamide

From 2,3-dichlorobenzoic acid and(4,4-difluoro-1-(4-methyl-1H-imidazol-1-yl)cyclohexyl)methanamine. LCMS(MH+): m/z=402.0, t_(R) (minutes, Method E)=0.45

Example 3h5N-(1-(1-(6-bromopyridin-3-yl)-4,4-difluorocyclohexyl)ethyl)-2,3-dichlorobenzamide

From 2,3-dichlorobenzoic acid and1-(1-(6-bromopyridin-3-yl)-4,4-difluorocyclohexyl)ethanamine. LCMS(MH+): m/z=493.1, t_(R) (minutes, Method D)=0.83

Example 3i52,3-dichloro-N((4,4-difluoro-1-(6-methylpyridin-3-yl)cyclohexyl)methyl)benzamide

From 2,3-dichlorobenzoic acid and(4,4-difluoro-1-(6-methylpyridin-3-yl)cyclohexyl)methanamine. LCMS(MH+): m/z=413.2, t_(R) (minutes, Method D)=0.51

Example 3j52-chloro-3-fluoro-N-((4,4-difluoro-1-(6-fluoropyridin-3-yl)cyclohexyl)methyl)benzamide

From 2-chloro-3-fluorobenzoic acid and(4,4-difluoro-1-(6-fluoropyridin-3-yl)cyclohexyl)methanamine. LCMS(MH+): m/z=401.2, t_(R) (minutes, Method D)=0.72

Example 3163-chloro-N-((4,4-difluoro-1-(6-fluoropyridin-3-yl)cyclohexyl)methyl)-2-fluorobenzamide

From 3-chloro-2-fluorobenzoic acid and(4,4-difluoro-1-(6-fluoropyridin-3-yl)cyclohexyl)methanamine. LCMS(MH+): m/z=401.2, t_(R) (minutes, Method D)=0.75

Example 3152-chloro-N-((4,4-difluoro-1-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)methyl)benzamide

From 2-chlorobenzoic acid and(4,4-difluoro-1-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)methanamine.LCMS (MH+): m/z=433.2, t_(R) (minutes, Method D)=0.78

Example 3m52-chloro-3-methoxy-N-((4,4-difluoro-1-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)methyl)benzamide

From 2-chloro-3-methoxybenzoic acid and(4,4-difluoro-1-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)methanamine.LCMS (MH+): m/z=463.2, t_(R) (minutes, Method D)=0.77

Example 3n52-chloro-3-fluoro-N-((4,4-difluoro-1-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)methyl)benzamide

From 2-chloro-3-fluorobenzoic acid and(4,4-difluoro-1-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)methanamine.LCMS (MH+): m/z=451.2, t_(R) (minutes, Method D)=0.79

Example 3o53-chloro-N-((4,4-difluoro-1-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)methyl)-2-fluorobenzamide

From 3-chloro-2-fluorobenzoic acid and(4,4-difluoro-1-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)methanamine.LCMS (MH+): m/z=433.2, t_(R) (minutes, Method D)=0.83

Example 3p53-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-fluorobenzamide

From 3-chloro-2-fluorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS(MH+): m/z=401.2, t_(R) (minutes, Method D)=0.84

Example 3q52-chloro-4-fluoro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)benzamide

From 2-chloro-4-fluorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS(MH+): m/z=401.0, t_(R) (minutes, Method D)=0.79

Example 3r52,6-dichloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)benzamide

From 2,6-dichlorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS(MH+): m/z=417.2, t_(R) (minutes, Method D)=0.89

Example 3s52,6-dichloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propyl)benzamide

From 2,6-dichlorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS(MH+): m/z=418.1, t_(R) (minutes, Method D)=0.79

Example 3t52-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propyl)benzamide

From 2-chlorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS(MH+): m/z=384.1, t_(R) (minutes, Method D)=0.76

Example 3u52-chloro-3-fluoro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propyl)benzamide

From 2-chloro-3-fluorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS(MH+): m/z=402.1, t_(R) (minutes, Method D)=0.78

Example 3v52-chloro-6-fluoro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propyl)benzamide

From 2-chloro-6-fluorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS(MH+): m/z=402.1, t_(R) (minutes, Method D)=0.77

Example 3w52,4-dichloro-N-(2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2,4-dichlorobenzoic acid and2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+):m/z=439.0, t_(R) (minutes, Method E)=0.81

Example 3x52,3-dichloro-N4(3-(2-methylpyrimidin-5-yl)tetrahydrofuran-3-yl)methyl)benzamide

From 2,3-dichlorobenzoic acid and(3-(2-methylpyrimidin-5-yl)tetrahydrofuran-3-yl)methanamine. LCMS (MH+):m/z=366.0, t_(R) (minutes, Method E)=0.45

Example 3y52-Chloro-N-(2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+):m/z=405.2, t_(R) (minutes, Method D)=0.79

Example 3z52-chloro-6-fluoro-N-(2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+):m/z=423.1, t_(R) (minutes, Method D)=0.80

Example 3a62-chloro-3-fluoro-N-(2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+):m/z=423.1, t_(R) (minutes, Method D)=0.81

Example 3b62,3-dichloro-N-(2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+):m/z=439.2, t_(R) (minutes, Method D)=0.84

Example 3c62-Chloro-N-(3-cyclopropyl-2-(5-methylpyrazin-2-yl)propyl)benzamide

From 2-chlorobenzoic acid and3-cyclopropyl-2-(5-methylpyrazin-2-yl)propylamine. LCMS (MH+):m/z=330.0, t_(R) (minutes, Method E)=0.61

Example 3d62-Chloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine.LCMS (MH+): m/z=413.0, t_(R) (minutes, Method E)=0.64

Example 3e62-Chloro-3-fluoro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine.LCMS (MH+): m/z=431.2, t_(R) (minutes, Method D)=0.69

Example 3f62,3-Dichloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine.LCMS (MH+): m/z=447.0, t_(R) (minutes, Method E)=0.70

Example 3g62-Chloro-6-fluoro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine.LCMS (MH+): m/z=431.0, t_(R) (minutes, Method E)=0.64

Example 3h62-Chloro-N-(2-isopropoxy-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and2-isopropoxy-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+):m/z=334.0, t_(R) (minutes, Method E)=0.52

Example 3i62,3-Dichloro-N-(2-isopropoxy-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-isopropoxy-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+):m/z=368.1, t_(R) (minutes, Method D)=0.64

Example 3j62,3-Dichloro-N-(2-(1-methyl-1H-pyrazol-4-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(1-methyl-1H-pyrazol-4-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine.LCMS (MH+): m/z=382.0, t_(R) (minutes, Method E)=0.52

Example 3k62,3-Dichloro-N4(2-(2-methylpyrimidin-5-yl)tetrahydrofuran-2-yl)methyl)benzamide

From 2,3-dichlorobenzoic acid and(2-(2-methylpyrimidin-5-yl)tetrahydrofuran-2-yl)methanamine. LCMS (MH+):m/z=366.0, t_(R) (minutes, Method E)=0.52

Example 3162,3-Dichloro-N-(2-(1-methyl-1H-pyrazol-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and2-(1-methyl-1H-pyrazol-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine.LCMS (MH+): m/z=443.2, t_(R) (minutes, Method D)=0.67

Example 3m62,3-Dichloro-N-[2-(1-methylpyrazol-4-yl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide

From 2,3-dichlorobenzoic acid and2-(1-methyl-1H-pyrazol-4-yl)-2-(6-(trifluoromethyl)pyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=444.1, t_(R) (minutes, Method F)=2.73

Example 3n62,3-dichloro-N-[2-(1-methylpyrazol-3-yl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide

From 2,3-dichlorobenzoic acid and2-(1-methyl-1H-pyrazol-3-yl)-2-(6-(trifluoromethyl)pyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=444.1, t_(R) (minutes, Method F)=2.87

Example 3o62,3-Dichloro-N-[2-(1-methyl-1H-imidazol-4-yl)-2-(2-trifluoromethyl-pyrimidin-5-yl)-ethyl]-benzamide

From 2,3-dichlorobenzoic acid and2-(1-methyl-1H-imidazol-4-yl)-2-(6-(trifluoromethyl)pyrimidin-5-yl)ethanamine.LCMS (MH+): m/z=443.8, t_(R) (minutes, Method F)=1.97

Example 3p62-Chloro-N-((4,4-difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)-3-methoxybenzamide

From 2-chloro-3-methoxybenzoic acid and[4,4-Difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl]methanamine.LCMS (MH+): m/z=464.1, t_(R) (minutes, Method F)=3.02

Example 3q62-Chloro-N-[[4,4-difluoro-1-[2-(trifluoromethyl)pyrimidin-5-yl]cyclohexyl]methyl]benzamide

From 2-chlorobenzoic acid and[4,4-Difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl]methanamine.LCMS (MH+): m/z=434.1, t_(R) (minutes, Method F)=3.04

Example 3r62-Chloro-N-((4,4-difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)-3-fluorobenzamide

From 2-chloro-3-fluorobenzoic acid and[4,4-Difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl]methanamine.LCMS (MH+): m/z=452.1, t_(R) (minutes, Method F)=3.08

Example 3s62-Chloro-N-((4,4-difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)-3-(trifluoromethyl)benzamide

From 2-chloro-3-trifluoromethylbenzoic acid and[4,4-Difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl]methanamine.LCMS (MH+): m/z=502.1, t_(R) (minutes, Method F)=3.25

Example 3t62-Chloro-N-((4,4-difluoro-1-(2-(difluoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)-3-methoxybenzamide

From 2-chloro-3-methoxybenzoic acid and(1-(2-(difluoromethyl)pyrimidin-5-yl)-4,4-difluorocyclohexyl)methanamine.LCMS (MH+): m/z=446.1, t_(R) (minutes, Method F)=2.82

Example 3u62-Chloro-N-((4,4-difluoro-1-(2-(difluoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)benzamide

From 2-chlorobenzoic acid and(1-(2-(difluoromethyl)pyrimidin-5-yl)-4,4-difluorocyclohexyl)methanamine.LCMS (MH+): m/z=416.1, t_(R) (minutes, Method F)=2.83

Example 3v62,3-dichloro-N-((4,4-difluoro-1-(2-(difluoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)benzamide

From 2,3-dichlorobenzoic acid and(1-(2-(difluoromethyl)pyrimidin-5-yl)-4,4-difluorocyclohexyl)methanamine.LCMS (MH+): m/z=450.1, t_(R) (minutes, Method F)=2.98

Example 3w62-Chloro-N-((4,4-difluoro-1-(2-(difluoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)-3-fluorobenzamide

From 2-chloro-3-fluorobenzoic acid(1-(2-(difluoromethyl)pyrimidin-5-yl)-4,4-difluorocyclohexyl)methanamine.LCMS (MH+): m/z=434.1, t_(R) (minutes, Method F)=2.88

Example 3x62-Chloro-N-((4,4-difluoro-1-(2-(difluoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)-3-(trifluoromethyl)benzamide

From 2-chloro-3-trifluoromethylbenzoic(1-(2-(difluoromethyl)pyrimidin-5-yl)-4,4-difluorocyclohexyl)methanamine.LCMS (MH+): m/z=484.0, t_(R) (minutes, Method F)=3.07

Example 3y62,6-dichloro-N((4,4-difluoro-1-(2-(difluoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)benzamide

From 2,6-dichlorobenzoic acid and(1-(2-(difluoromethyl)pyrimidin-5-yl)-4,4-difluorocyclohexyl)methanamine.LCMS (MH+): m/z=450.1, t_(R) (minutes, Method F)=2.93

Example 4a(+)-2-Chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

The racemic mixture which was prepared as described for example 3c1 wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=383.1, t_(R) (minutes, Method G)=2.5. [α]_(D)²⁰=+13.66 (c=3.0 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4b(−)-2-Chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

LCMS (MH+): m/z=383.1, t_(R) (minutes, Method G)=2.5. [α]_(D) ²⁰=−13.0(c=3.0 mg/mL, CHCl₃)

Example 4c(+)-2,3-Dichloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

The racemic mixture which was prepared as described for example 3a wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=417.1, t_(R) (minutes, Method G)=2.64. [α]_(D)²⁰=+15.0 (c=3.0 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4d(−)-2,3-Dichloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

LCMS (MH+): m/z=417.1, t_(R) (minutes, Method G)=2.64. [α]_(D) ²⁰=−12.0(c=3.0 mg/mL, CHCl₃)

Example 4e(+)-2-Chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]-3-(trifluoromethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-trifluoromethylbenzoic acid and3-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=451.1, t_(R) (minutes, Method G)=3.11. [α]_(D)²⁰=+26.0 (c=2.0 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4f(−)-2-Chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]-3-(trifluoromethyl)benzamide

LCMS (MH+): m/z=451.1, t_(R) (minutes, Method G)=3.11. [α]_(D) ²⁰=−25.0(c=2.0 mg/mL, CHCl₃)

Example 4g(−)-2,3-Dichloro-N-[2-(2-methylpyrimidin-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propyl]benzamide

The racemic mixture which was prepared as described for example 3a wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=432.0, t_(R) (minutes, Method F)=2.72. [α]_(D)²⁰=−34.0 (c=4.5 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4h(+)-2,3-Dichloro-N-[2-(2-methylpyrimidin-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propyl]benzamide

LCMS (MH+): m/z=432.0, t_(R) (minutes, Method F)=2.72. [α]_(D) ²⁰=35.7(c=4.7 mg/mL, CHCl₃)

Example 4i(−)-2-Chloro-N-[2-(2-methylpyrimidin-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propyl]benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and2-(2-methyl-pyrimidin-5-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine was separated into the two enantiomers by preparative SFCto yield the title compound. LCMS (MH+): m/z=398.1, t_(R) (minutes,Method F)=2.55. [α]_(D) ²⁰=−25.5 (c=5.1 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4j(+)-2-Chloro-N-[2-(2-methylpyrimidin-5-yl)-3-[1-(trifluoromethyl)cyclopropyl]propyl]benzamide

LCMS (MH+): m/z=398.1, t_(R) (minutes, Method F)=2.55. [α]_(D) ²⁰=27.1(c=5.5 mg/mL, CHCl₃)

Example 4k(+)-2-Chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]-3-methoxy-benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-methoxybenzoic acid and3-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=413.1, t_(R) (minutes, Method G)=2.84. [α]_(D)²⁰=+20.9 (c=0.86 mg/mL, CHCl₃)

Example 4l(−)-2-Chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]-3-methoxy-benzamide

LCMS (MH+): m/z=413.1, t_(R) (minutes, Method G)=2.84. [α]_(D) ²⁰=−22.09(c=0.86 mg/mL, CHCl₃)

Example 4m(−)-2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-6-fluorobenzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-6-fluorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=401.1, t_(R) (minutes, Method G)=2.88. [α]_(D)²⁰=−25.9 (c=0.81 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4n(+)-2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-6-fluorobenzamide

LCMS (MH+): m/z=401.1, t_(R) (minutes, Method G)=2.88. [α]_(D) ²⁰=25.9(c=0.81 mg/mL, CHCl₃)

Example 4o(−)-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-methoxybenzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-methoxybenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=379.1, t_(R) (minutes, Method G)=3.01. [α]_(D)²⁰=−6.67 (c=3.9 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4p(+)-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-methoxybenzamide

LCMS (MH+): m/z=379.1, t_(R) (minutes, Method G)=3.01. [α]_(D) ²⁰=6.89(c=4.5 mg/mL, CHCl₃)

Example 4q(−)-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2,6-difluorobenzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,6-difluorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=385.1, t_(R) (minutes, Method G)=2.92. [α]_(D)²⁰=−35.71 (c=0.84 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4r(+)-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2,6-difluorobenzamide

LCMS (MH+): m/z=385.1, t_(R) (minutes, Method G)=2.92. [α]_(D) ²⁰==36.9(c=0.84 mg/mL, CHCl₃)

Example 4s(+)-2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-5-(methylsulfonyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-5-(methylsulfonyl)benzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=461.1, t_(R) (minutes, Method F)=2.98. [α]_(D)²⁰=+28.75 (c=0.8 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4t(−)-2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-5-(methylsulfonyl)benzamide

LCMS (MH+): m/z=461.1, t_(R) (minutes, Method F)=2.98. [α]_(D) ²⁰=−27.0(c=1.0 mg/mL, CHCl₃)

Example 4u(+)-2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-3-fluorobenzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-fluorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=401.1, t_(R) (minutes, Method G)=2.61. [α]_(D)²⁰=+28.13 (c=1.6 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4v(−)-2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-3-fluorobenzamide

LCMS (MH+): m/z=401.1, t_(R) (minutes, Method G)=2.61. [α]_(D) ²⁰=−26.25(c=1.6 mg/mL, CHCl₃)

Example 4w(+)-2-chloro-N-(3-cyclopropyl-2-(6-fluoropyridin-3-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and3-cyclopropyl-2-(6-fluoropyridin-3-yl)propan-1-amine was separated intothe two enantiomers by preparative SFC to yield the title compound. LCMS(MH+): m/z=333.1, t_(R) (minutes, Method F)=2.53. [α]_(D) ²⁰=+29.0(c=2.0 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4x(−)-2-chloro-N-(3-cyclopropyl-2-(6-fluoropyridin-3-yl)propyl)benzamide

LCMS (MH+): m/z=333.1, t_(R) (minutes, Method F)=2.53. [α]_(D) ²⁰=−24.5(c=2.0 mg/mL, CHCl₃)

Example 4y(+)-2,3-dichloro-N-(3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propan-1-amine was separatedinto the two enantiomers by preparative SFC to yield the title compoundLCMS (MH+): m/z=364.1, t_(R) (minutes, Method F)=2.64. [α]_(D) ²⁰=+41.3(c=1.5 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4z(−)-2,3-dichloro-N-(3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=364.1, t_(R) (minutes, Method F)=2.64. [α]_(D) ²⁰=−40.7(c=1.5 mg/mL, CHCl₃)

Example 4a1(+)-2,3-dichloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=418.1, t_(R) (minutes, Method G)=2.59. [α]_(D)²⁰=+21.41 (c=3.27 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4b1(−)-2,3-dichloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=418.1, t_(R) (minutes, Method G)=2.59. [α]_(D) ²⁰=−22.00(c=3.0 mg/mL, CHCl₃)

Example 4c1(+)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=384.1, t_(R) (minutes, Method F)=2.66. [α]_(D)²⁰=+23.68 (c=5.49 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4d1(−)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=384.1, t_(R) (minutes, Method F)=2.66. [α]_(D) ²⁰=−21.63(c=5.27 mg/mL, CHCl₃)

Example 4e1(+)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3-fluorobenzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-fluorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=402.1, t_(R) (minutes, Method F)=2.71. [α]_(D)²⁰=+24.77 (c=4.44 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4f1(−)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3-fluorobenzamide

LCMS (MH+): m/z=402.1, t_(R) (minutes, Method F)=2.71. [α]_(D) ²⁰=−21.77(c=4.50 mg/mL, CHCl₃)

Example 4g1(+)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-6-fluorobenzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-6-fluorobenzoic acid and3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=402.1, t_(R) (minutes, Method F)=2.69. [α]_(D)²⁰=+35.56 (c=2.25 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4h1(−)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-6-fluorobenzamide

LCMS (MH+): m/z=402.1, t_(R) (minutes, Method F)=2.69. [α]_(D) ²⁰=−34.27(c=2.48 mg/mL, CHCl₃)

Example 4i1(+)-2,3-dichloro-N-(3-cyclopropyl-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and2-(5-(1-amino-3-cyclopropylpropan-2-yl)pyridin-2-yl)propan-2-ol wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=407.1, t_(R) (minutes, Method F)=1.98. [α]_(D)²⁰=+23.89 (c=3.0 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4j1(−)-2,3-dichloro-N-(3-cyclopropyl-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)propyl)benzamide

LCMS (MH+): m/z=407.1, t_(R) (minutes, Method F)=1.98. [α]_(D) ²⁰=−28.17(c=3.1 mg/mL, CHCl₃)

Example 4k1(+)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3-methoxybenzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-methoxybenzoic acid and3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=414.0, t_(R) (minutes, Method F)=2.53. [α]_(D)²⁰=+26.3 (c=4.0 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4l1(−)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3-methoxybenzamide

LCMS (MH+): m/z=414.0, t_(R) (minutes, Method F)=2.53. [α]_(D) ²⁰=−29.5(c=3.7 mg/mL, CHCl₃)

Example 4m1(+)-2-methyl-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3-methoxybenzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-methyl-3-methoxybenzoic acid and3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=394.0, t_(R) (minutes, Method F)=2.59. [α]_(D)²⁰=+26.8 (c=3.90 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4n1(−)-2-methyl-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3-methoxybenzamide

LCMS (MH+): m/z=394.0, t_(R) (minutes, Method F)=2.59. [α]_(D) ²⁰=−26.9(c=3.40 mg/mL, CHCl₃)

Example 4o1(+)-2,6-dichloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,6-dichlorobenzoic acid and3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=418.1, t_(R) (minutes, Method F)=2.62. [α]_(D)²⁰=+21.87 (c=3.2 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4p1(−)-2,6-dichloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=418.1, t_(R) (minutes, Method F)=2.62. [α]_(D) ²⁰=−21.43(c=2.8 mg/mL, CHCl₃)

Example 4q1(+)-2,6-dichloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyridin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,6-dichlorobenzoic acid and3-cyclopropyl-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound LCMS (MH+): m/z=417.1, t_(R) (minutes, Method G)=2.50. [α]_(D)²⁰=+20.64 (c=4.7 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4r1(−)-2,6-dichloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyridin-5-yl)propyl)benzamide

LCMS (MH+): m/z=417.1, t_(R) (minutes, Method G)=2.50. [α]_(D) ²⁰=−20.3(c=3.5 mg/mL, CHCl₃)

Example 4s1(+)-2,6-dichloro-N-(3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,6-dichlorobenzoic acid and3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propan-1-amine was separatedinto the two enantiomers by preparative SFC to yield the title compound.LCMS (MH+): m/z=364.1, t_(R) (minutes, Method F)=2.43. [α]_(D) ²⁰=+15.42(c=2.4 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4t1(−)-2,6-dichloro-N-(3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=364.1, t_(R) (minutes, Method F)=2.43. [α]_(D) ²⁰=−11.51(c=1.87 mg/mL, CHCl₃)

Example 4u1 (+)-2-chloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=398.1, t_(R) (minutes, Method F)=2.62.[α]_(D) ²⁰=+13.77 (c=5.30 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4v1(−)-2-chloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=398.1, t_(R) (minutes, Method F)=2.62. [α]_(D) ²⁰=−14.16(c=5.86 mg/mL, CHCl₃)

Example 4x1(+)-2-chloro-3-fluoro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-fluorobenzoic acid and3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=416.1, t_(R) (minutes, Method G)=2.48.[α]_(D) ²⁰=+13.80 (c=5.87 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4y1(−)-2-chloro-3-fluoro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=416.1, t_(R) (minutes, Method G)=2.48. [α]_(D) ²⁰=−13.85(c=5.63 mg/mL, CHCl₃)

Example 4z1(+)-2,3-dichloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=432.1, t_(R) (minutes, Method G)=2.58.[α]_(D) ²⁰=+17.42 (c=6.6 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4a2(−)-2,3-dichloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=432.1, t_(R) (minutes, Method G)=2.58. [α]_(D) ²⁰=−17.32(c=6.6 mg/mL, CHCl₃)

Example 4b2(+)-2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=360.1, t_(R) (minutes, Method F)=1.9711.65.[α]_(D) ²⁰=+43.43 (c=1.75 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4c2(−)-2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

LCMS (MH+): m/z=360.1, t_(R) (minutes, Method F)=1.97. [α]_(D) ²⁰=−38.00(c=1.5 mg/mL, CHCl₃)

Example 4d2(+)-2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound LCMS (MH+): m/z=394.1, t_(R) (minutes, Method F)=1.88. [α]_(D)²⁰=+57.50 (c=2.0 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4e2(−)-2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

LCMS (MH+): m/z=394.1, t_(R) (minutes, Method F)=1.88. [α]_(D) ²⁰=−57.89(c=1.9 mg/mL, CHCl₃)

Example 4l2(+)-2-chloro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=452.0, t_(R) (minutes, Method F)=3.03.[α]_(D) ²⁰=+27.50 (c=4.80 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4g2(−)-2-chloro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=452.0, t_(R) (minutes, Method F)=3.03. [α]_(D) ²⁰=−27.32(c=3.88 mg/mL, CHCl₃)

Example 4h2(+)-2,3-dichloro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=486.1, t_(R) (minutes, Method F)=2.77.[α]_(D) ²⁰=+31.03 (c=5.80 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4i2(−)-2,3-dichloro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=486.1, t_(R) (minutes, Method F)=2.77. [α]_(D) ²⁰=−31.87(c=5.02 mg/mL, CHCl₃)

Example 4j2(+)-2-chloro-3-fluoro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-fluorobenzoic acid and3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=470.0, t_(R) (minutes, Method F)=3.07.[α]_(D) ²⁰=+28.85 (c=3.05 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4k2(−)-2-chloro-3-fluoro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=470.0, t_(R) (minutes, Method F)=3.07. [α]_(D) ²⁰=−28.97(c=3.21 mg/mL, CHCl₃)

Example 4l2(+)-2-chloro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=451.1, t_(R) (minutes, Method G)=2.50.[α]_(D) ²⁰=+33.55 (c=3.07 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4m2(−)-2-chloro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propyl)benzamide

LCMS (MH+): m/z=451.1, t_(R) (minutes, Method G)=2.50. [α]_(D) ²⁰=−32.98(c=3.20 mg/mL, CHCl₃)

Example 4n2(+)-2,3-dichloro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=485.1, t_(R) (minutes, Method G)=2.63.[α]_(D) ²⁰=+27.63 (c=1.52 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4o2(−)-2,3-dichloro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propyl)benzamide

LCMS (MH+): m/z=485.1, t_(R) (minutes, Method G)=2.63. [α]_(D) ²⁰=−26.67(c=1.50 mg/mL, CHCl₃)

Example 4p2(+)-2-chloro-3-fluoro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-fluorobenzoic acid and3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=469.1, t_(R) (minutes, Method G)=2.54.[α]_(D) ²⁰=+27.60 (c=3.20 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4q2(−)-2-chloro-3-fluoro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propyl)benzamide

LCMS (MH+): m/z=469.1, t_(R) (minutes, Method G)=2.54. [α]_(D) ²⁰=−27.55(c=3.40 mg/mL, CHCl₃)

Example 4r2(+)-2,3-dichloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanaminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=448.0, t_(R) (minutes, Method F)=2.72.[α]_(D) ²⁰=+42.52 (c=3.8 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4s2(−)-2,3-dichloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH+): m/z=448.0, t_(R) (minutes, Method F)=2.72. [α]_(D) ²⁰=−42.62(c=3.66 mg/mL, CHCl₃)

Example 4t2(+)-2-chloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanaminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=414.1, t_(R) (minutes, Method F)=2.54.[α]_(D) ²⁰=+38.57 (c=2.80 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4u2(−)-2-chloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH+): m/z=414.1, t_(R) (minutes, Method F)=2.54. [α]_(D) ²⁰=−38.13(c=3.20 mg/mL, CHCl₃)

Example 4v2(+)-2-chloro-3-fluoro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-fluorobenzoic acid and2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanaminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=432.1, t_(R) (minutes, Method F)=2.48.[α]_(D) ²⁰=+32.38 (c=3.27 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4x2(−)-2-chloro-3-fluoro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH+): m/z=432.1, t_(R) (minutes, Method F)=2.48. [α]_(D) ²⁰=−35.64(c=3.18 mg/mL, CHCl₃)

Example 4y2(+)-2-chloro-6-fluoro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-6-fluorobenzoic acid and2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanaminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=432.1, t_(R) (minutes, Method F)=2.6.[α]_(D) ²⁰=+37.86 (c=4.20 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4z2(−)-2-chloro-6-fluoro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH+): m/z=432.1, t_(R) (minutes, Method F)=2.6. [α]_(D) ²⁰=−37.86(c=3.83 mg/mL, CHCl₃)

Example 4a3(+)-2,6-dichloro-N-(2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,6-dichlorobenzoic acid and2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine was separatedinto the two enantiomers by preparative SFC to yield the title compound.LCMS (MH+): m/z=439.1, t_(R) (minutes, Method G)=2.76. [α]_(D) ²⁰=+3.18(c=6.38 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4b3(−)-2,6-dichloro-N-(2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

LCMS (MH+): m/z=439.1, t_(R) (minutes, Method G)=2.76. [α]_(D) ²⁰=−4.19(c=7.8 mg/mL, CHCl₃)

Example 4c3(+)-2,3-dichloro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=457.0, t_(R) (minutes, Method G)=3.02. [α]_(D)²⁰=+4.17 (c=3.04 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4d3(−)-2,3-dichloro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

LCMS (MH+): m/z=457.0, t_(R) (minutes, Method G)=3.02. [α]_(D) ²⁰=−4.31(c=3.64 mg/mL, CHCl₃)

Example 4e3(+)-2-chloro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=423.1, t_(R) (minutes, Method G)=2.58. [α]_(D)²⁰=+18.1 (c=5.22 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4l3(−)-2-chloro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

LCMS (MH+): m/z=423.1, t_(R) (minutes, Method G)=2.58. [α]_(D) ²⁰=−16.1(c=5.26 mg/mL, CHCl₃)

Example 4g3(+)-2-chloro-3-fluoro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-fluorobenzoic acid and2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=441.1, t_(R) (minutes, Method G)=2.63. [α]_(D)²⁰=+10.60 (c=5.6 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4h3(−)-2-chloro-3-fluoro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

LCMS (MH+): m/z=441.1, t_(R) (minutes, Method G)=2.63. [α]_(D) ²⁰=−10.96(c=5.2 mg/mL, CHCl₃)

Example 4i3(+)-2-chloro-6-fluoro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-6-fluorobenzoic acid and2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound LCMS (MH+): m/z=441.0, t_(R) (minutes, Method G)=2.86. [α]_(D)²⁰=+17.1 (c=4.44 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4j3(−)-2-chloro-6-fluoro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

LCMS (MH+): m/z=441.0, t_(R) (minutes, Method G)=2.86. [α]_(D) ²⁰=−15.7(c=4.58 mg/mL, CHCl₃)

Example 4k3(+)-2,3-dichloro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=458.0, t_(R) (minutes, Method G)=2.91. [α]_(D)²⁰=+14.2 (c=8.50 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4l3(−)-2,3-dichloro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH+): m/z=458.0, t_(R) (minutes, Method G)=2.91. [α]_(D) ²⁰=−14.3(c=7.90 mg/mL, CHCl₃)

Example 4m3(+)-2-chloro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=424.1, t_(R) (minutes, Method F)=3.19. [α]_(D)²⁰=+16.4 (c=6.80 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4n3(−)-2-chloro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH+): m/z=424.1, t_(R) (minutes, Method F)=3.19. [α]_(D) ²⁰=−14.3(c=6.40 mg/mL, CHCl₃)

Example 4o3(+)-2-chloro-3-fluoro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-fluorobenzoic acid and2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=442.1, t_(R) (minutes, Method F)=3.24. [α]_(D)²⁰=+12.8 (c=6.8 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4p3(−)-2-chloro-3-fluoro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH+): m/z=442.1, t_(R) (minutes, Method F)=3.24. [α]_(D) ²⁰=−12.3(c=7.0 mg/mL, CHCl₃)

Example 4q3(+)-2-chloro-6-fluoro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-6-fluorobenzoic acid and2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=442.0, t_(R) (minutes, Method F)=2.99. [α]_(D)²⁰=+18.1 (c=4.0 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4r3(−)-2-chloro-6-fluoro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH+): m/z=442.0, t_(R) (minutes, Method F)=2.99. [α]_(D) ²⁰=−16.1(c=4.0 mg/mL, CHCl₃)

Example 4s3(+)-2-chloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanaminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=448.1, t_(R) (minutes, Method F)=2.95.[α]_(D) ²⁰=+28.00 (c=1.5 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4t3(−)-2-chloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH+): m/z=448.1, t_(R) (minutes, Method F)=2.95. [α]_(D) ²⁰=−28.83(c=1.63 mg/mL, CHCl₃)

Example 4u3(+)-2,3-dichloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanaminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=482.1, t_(R) (minutes, Method G)=2.76.[α]_(D) ²⁰=+24.29 (c=0.70 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4v3(−)-2,3-dichloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH+): m/z=482.1, t_(R) (minutes, Method G)=2.76. [α]_(D) ²⁰=−23.46(c=0.81 mg/mL, CHCl₃)

Example 4x3(+)-2-chloro-6-fluoro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-6-fluorobenzoic acid and2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanaminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=466.1, t_(R) (minutes, Method F)=2.97.[α]_(D) ²⁰=+36.00 (c=1.50 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4y3(−)-2-chloro-6-fluoro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH+): m/z=466.1, t_(R) (minutes, Method F)=2.97. [α]_(D) ²⁰=−34.89(c=1.50 mg/mL, CHCl₃)

Example 4z3(+)-2-chloro-3-fluoro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-fluorobenzoic acid and2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanaminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=466.1, t_(R) (minutes, Method F)=2.67.[α]_(D) ²⁰=+28.57 (c=0.56 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4a4(−)-2-chloro-3-fluoro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH+): m/z=466.1, t_(R) (minutes, Method F)=2.67. [α]_(D) ²⁰=−28.83(c=0.61 mg/mL, CHCl₃)

Example 4b4(+)-2,3-dichloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=448.1, t_(R) (minutes, Method F)=2.95. [α]_(D)²⁰=+49.6 (c=4.8 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4c4(−)-2,3-dichloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z=448.1, t_(R) (minutes, Method F)=2.95. [α]_(D) ²⁰=−47.0(c=5.20 mg/mL, CHCl₃)

Example 4d4(+)-2-chloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=365.1, t_(R) (minutes, Method F)=2.97. [α]_(D)²⁰=+21.00 (c=3.00 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4e4(−)-2-chloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

LCMS (MH+): m/z=365.1, t_(R) (minutes, Method F)=2.97. [α]_(D) ²⁰=−20.00(c=2.90 mg/mL, CHCl₃)

Example 4f4(+)-2,3-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=399.1, t_(R) (minutes, Method G)=2.57. [α]_(D)²⁰=+20.45 (c=2.20 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4g4(−)-2,3-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

LCMS (MH+): m/z=399.1, t_(R) (minutes, Method G)=2.57. [α]_(D) ²⁰=−19.43(c=2.11 mg/mL, CHCl₃)

Example 4h4(+)-2-chloro-3-fluoro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-fluorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=383.1, t_(R) (minutes, Method F)=3.02. [α]_(D)²⁰=+21.03 (c=2.90 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4i4(−)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyridin-5-yl)propyl)-6-fluorobenzamide

LCMS (MH+): m/z=383.1, t_(R) (minutes, Method F)=3.02. [α]_(D) ²⁰=−20.40(c=2.50 mg/mL, CHCl₃)

Example 4j4(+)-2-chloro-3-methoxy-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-methoxybenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=395.1, t_(R) (minutes, Method F)=2.96. [α]_(D)²⁰=+28.21 (c=2.80 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4k4(−)-2-chloro-3-methoxy-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

LCMS (MH+): m/z=395.1, t_(R) (minutes, Method F)=2.96. [α]_(D) ²⁰=−28.21(c=2.80 mg/mL, CHCl₃)

Example 4l4(+)-2,4-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,4-dichlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=399.1, t_(R) (minutes, Method G)=2.61. [α]_(D)²⁰=+29.58 (c=2.40 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4m4(−)-2,4-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

LCMS (MH+): m/z=399.1, t_(R) (minutes, Method G)=2.61. [α]_(D) ²⁰=−30.22(c=2.78 mg/mL, CHCl₃)

Example 4n4(+)-2,6-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,6-dichlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=399.1, t_(R) (minutes, Method F)=3.06. [α]_(D)²⁰=+31.97 (c=1.22 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4o4(−)-2,6-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

LCMS (MH+): m/z=399.1, t_(R) (minutes, Method F)=3.06. [α]_(D) ²⁰=−30.25(c=1.62 mg/mL, CHCl₃)

Example 4p4(+)-2-chloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=366.1, t_(R) (minutes, Method F)=2.84. [α]_(D)²⁰=+26.75 (c=2.43 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4q4(−)-2-chloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=366.1, t_(R) (minutes, Method F)=2.84 [α]_(D) ²⁰=−24.52(c=2.08 mg/mL, CHCl₃)

Example 4r4(+)-2,3-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=400.1, t_(R) (minutes, Method F)=3.00. [α]_(D)²⁰=+24.20 (c=2.81 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4s4(−)-2,3-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=400.1, t_(R) (minutes, Method F)=3.00. [α]_(D) ²⁰=−27.31(c=2.38 mg/mL, CHCl₃)

Example 4t4(+)-2-chloro-3-fluoro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-fluorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=384.1, t_(R) (minutes, Method F)=2.90. [α]_(D)²⁰=+20.59 (c=4.08 mg/mL, CHCl₃)

And the Corresponding enantiomer

Example 4u4(−)-2-chloro-3-fluoro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=384.1, t_(R) (minutes, Method F)=2.90. [α]_(D) ²⁰=−20.87(c=4.12 mg/mL, CHCl₃)

Example 4v4(+)-2-chloro-3-methoxy-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chloro-3-methoxybenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=396.1, t_(R) (minutes, Method F)=2.84. [α]_(D)²⁰=+24.50 (c=4.98 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4x4(−)-2-chloro-3-methoxy-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=396.1, t_(R) (minutes, Method F)=2.84. [α]_(D) ²⁰=−25.19(c=5.16 mg/mL, CHCl₃)

Example 4y4(+)-2,4-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,4-dichlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=400.1, t_(R) (minutes, Method F)=3.04. [α]_(D)²⁰=+28.45 (c=4.64 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4z4(−)-2,4-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=400.1, t_(R) (minutes, Method F)=3.04. [α]_(D) ²⁰=−28.60(c=4.79 mg/mL, CHCl₃)

Example 4a5(+)-2,6-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,6-dichlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-1-amine wasseparated into the two enantiomers by preparative SFC to yield the titlecompound. LCMS (MH+): m/z=400.1, t_(R) (minutes, Method F)=2.93. [α]_(D)²⁰=+18.43 (c=3.58 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4b5(−)-2,6-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z=400.1, t_(R) (minutes, Method F)=2.93. [α]_(D) ²⁰=−18.51(c=4.16 mg/mL, CHCl₃)

Example 4c5(+)-2-chloro-N-[(3-cyclopropyl-2-[2-(difluoromethyl)pyrimidin-5-yl]-2-methyl-propyl]benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)-2-methyl-propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=380.1, t_(R) (minutes, Method F)=2.82.[α]_(D) ²⁰=+11.73 (c=5.20 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4d5(−)-2-chloro-N-[(3-cyclopropyl-2-[2-(difluoromethyl)pyrimidin-5-yl]-2-methyl-propyl]benzamide

LCMS (MH+): m/z=380.1, t_(R) (minutes, Method F)=2.82. [α]_(D) ²⁰=−13.47(c=5.27 mg/mL, CHCl₃)

Example 4e5(+)-2,4-Dichloro-N-[(3-cyclopropyl-2-[2-(difluoromethyl)pyrimidin-5-yl]-2-methyl-propyl]benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,4-dichlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)-2-methyl-propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=414.1, t_(R) (minutes, Method F)=2.99.[α]_(D) ²⁰=+17.16 (c=5.07 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4f5(−)-2,4-Dichloro-N-[(3-cyclopropyl-2-[2-(difluoromethyl)pyrimidin-5-yl]-2-methyl-propyl]benzamide

LCMS (MH+): m/z=414.1, t_(R) (minutes, Method F)=2.99. [α]_(D) ²⁰=−17.55(c=5.30 mg/mL, CHCl₃)

Example 4g5(+)-2,3-Dichloro-N-[(3-cyclopropyl-2-[2-(difluoromethyl)pyrimidin-5-yl]-2-methyl-propyl]benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)-2-methyl-propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=414.1, t_(R) (minutes, Method F)=2.96.[α]_(D) ²⁰=+18.40 (c=6.63 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4h5(−)-2,3-Dichloro-N-[(3-cyclopropyl-2-[2-(difluoromethyl)pyrimidin-5-yl]-2-methyl-propyl]benzamide

LCMS (MH+): m/z=414.1, t_(R) (minutes, Method F)=2.96. [α]_(D) ²⁰=−20.13(c=5.91 mg/mL, CHCl₃)

Example 4i5(+)-2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=384.1, t_(R) (minutes, Method F)=2.72.[α]_(D) ²⁰=+21.30 (c=2.39 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4j5(−)-2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propyl)benzamide

LCMS (MH+): m/z=384.1, t_(R) (minutes, Method F)=2.72. [α]_(D) ²⁰=−20.80(c=2.02 mg/mL, CHCl₃)

Example 4k5(+)-2,4-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,4-dichlorobenzoic acid and2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=418.1, t_(R) (minutes, Method F)=2.93.[α]_(D) ²⁰=+25.40 (c=3.42 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4l5(−)-2,4-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propyl)benzamide

LCMS (MH+): m/z=418.1, t_(R) (minutes, Method F)=2.93. [α]_(D) ²⁰=−29.5(c=2.71 mg/mL, CHCl₃)

Example 4m5(+)-2,3-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=418.1, t_(R) (minutes, Method F)=2.89.[α]_(D) ²⁰=+21.70 (c=3.00 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4n5(−)-2,3-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propyl)benzamide

LCMS (MH+): m/z=418.1, t_(R) (minutes, Method F)=2.89. [α]_(D) ²⁰=−23.7(c=3.20 mg/mL, CHCl₃)

Example 4o5(+)-2-Chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2-chlorobenzoic acid and2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=434.0, t_(R) (minutes, Method F)=2.42.[α]_(D) ²⁰=+25.30 (c=3.75 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4p5(−)-2-Chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propyl)benzamide

LCMS (MH+): m/z=434.0, t_(R) (minutes, Method F)=2.72. [α]_(D) ²⁰=−28.50(c=3.86 mg/mL, CHCl₃)

Example 4q5(+)-2,4-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,4-dichlorobenzoic acid and2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=468.0, t_(R) (minutes, Method F)=3.14.[α]_(D) ²⁰=+32.40 (c=3.15 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4r5(−)-2,4-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propyl)benzamide

LCMS (MH+): m/z=468.0, t_(R) (minutes, Method F)=3.14. [α]_(D) ²⁰=45.3(c=2.76 mg/mL, CHCl₃)

Example 4s5(+)-2,3-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3afrom 2,3-dichlorobenzoic acid and2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-aminewas separated into the two enantiomers by preparative SFC to yield thetitle compound. LCMS (MH+): m/z=468.0, t_(R) (minutes, Method F)=2.84.[α]_(D) ²⁰=+27.80 (c=3.41 mg/mL, CHCl₃)

And the corresponding enantiomer

Example 4t5(−)-2,3-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propyl)benzamide

LCMS (MH+): m/z=468.0, t_(R) (minutes, Method F)=2.57. [α]_(D) ²⁰=−35.8(c=2.37 mg/mL, CHCl₃)

Example 5 P2X₇ Binding Assay

This example illustrates representative assays for use in evaluating thetest compounds for antagonist activity. Compounds of the presentinvention were tested in vitro for their ability to act as antagoniststo the P2X₇ receptor.

Screening assays to determine P2X₇ receptor antagonism are well known tothe person skilled in the art. Functional assays, such as secondmessenger assays, and cytokine measurement assays done in vitro are alsowell known in the art and may be used to assess the specific binding andcellular activity of P2X₇ receptor compounds.

In Vitro Assay Example

Cell culture: 293 HEK cells, stably transfected with plasmids capable ofexpressing human P2X₇ receptor, were cultured by standard methods. Cellswere plated to cell density of approximately 15,000 cells/well in384-well assay plates (50 μl/well) with 1.5% low serum media (DMEM, 1.5%BCS, 1% L-glut (2 mM), 1% P/S).

293 HEK cells, stably transfected with plasmids capable of expressingrat or mouse P2X7 receptor, were cultured by standard methods. Cellswere plated to cell density of approximately 15,000 cells/well in384-well assay plates (50 μl/well) with 1.5% low serum media (DMEM, 1.5%FBS, 1% L-glut (2 mM), 10 mM HEPES, 1% P/S). Cells were plated 24 hoursprior to assay. Cells expressing human, rat or mouse P2X7 receptor wereassayed in the following manner.

Fluorescent Imaging Plate Reader (FLIPR) assay: Briefly, 293-human ormouse P2X₇ stable cells were incubated in sucrose buffer, pH 7.4 [KCl (5mM), NaH₂PO₄.2H₂O (9.6 mM), HEPES (25 mM), sucrose (280 mM), glucose (5mM), CaCl₂ (0.5 mM), and probenecid (0.1425 g in 3 mL 1N NaOH was addedfor 500 mL solution)] in 384-well plates.

293-rat P2X₇ stable cells were incubated in HHPB (pH 7.4) [consisting ofHank's BSS (1×); HEPES (pH 7.4) (20 mM) (Sigma); probenecid (0.710 g/5mL 1N NaOH) (Sigma); and BSA (0.05%) (Roche) which was added after thepH had been adjusted] in 384-well plates. Fluo-4 NW dye mix (MolecularProbes, Inc., Eugene, Oreg., USA) was prepared in buffer (seemanufacturer's instructions). Cell plates were removed from the 37° C.incubator, the media discarded and then 30 μL of dye was added to eachwell. Plates were placed in the 37° C., non-CO₂ incubator for 30 minutesand then room temperature for 30 minutes.

Two sets of drug plates were prepared: A) Mixtures of compound plusagonist were prepared as follows, in order to determine dose response:BzATP: 11 point 112 log, diluted in buffer, starting from 1 mM. Testingcompounds: 11 point 112 log, diluted in 2% DMSO buffer starting from 10μM. B) Agonist only mixture was prepared with BzATP at a singleconcentration in buffer (concentration determined by dose response).

Compound mixtures (A) were added to assay plates containing cells andplaced at room temperature for 30 minutes, then BzATP (B) was added.Fluorescence was read using the Tetra FLIPR® (Molecular Devices, Inc.,Sunnyvale, Calif., USA) and IC₅₀ values were calculated by standardmethods to determine antagonist activity.

Assay for stimulating IL1β release from THP-1 cells: THP-1 cells (TheGlobal Bioresource Center; ATCC #: TIB-2020 were differentiated byincubation with 10 ng/mL IFN-gamma (Sigma, Cat#: 13265) in T150 plates,at a cell density of 0.5 E⁶ cells/mL, in RPMI1640 media (ATCC,Cat#30-2001) with 10% FBS and 1% P/S for 48 hours. The cells then werestimulated with 100 ng/mL LPS (Sigma, Cat#: L4516) in serum free CTLTest media (Sigma Cat#: CTLT-005), without L-glutamine and antibiotics,for 3 hours. Test compounds (antagonists) were added and incubated for30 minutes. BzATP (at final concentration of 1 mM) was added andincubated for 30 minutes.

Cell plates were centrifuged at 3000 rpm for 5 minutes and thesupernatants were immediately collected for AlphaLISA® immunoassay(PerkinElmer Inc., Waltham, Mass., USA; Catalog No. AL220C) or aliquotedand stored at <−20° C. The AlphaLISA® immunoassay was performedaccording to the manufacturer's instructions.

TABLE 1 Exemplified IC₅₀ values of compounds of the invention: Chemicalname IC50 (nM) 2-Chloro-N-[4-(4-chloro-phenyl)-tetrahydro- 62pyran-4-ylmethyl]-5-methyl-benzamide2-Chloro-N-[4-(4-chloro-phenyl)-tetrahydro- 62pyran-4-ylmethyl]-5-methyl-benzamideN-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4- 170ylmethyl]-2,3-dimethyl-benzamideN-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4- 620ylmethyl]-2-methoxy-benzamide 2,6-Dichloro-N-[4-(4-chloro-phenyl)- 360tetrahydro-pyran-4-ylmethyl]-benzamideN-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4- 2100ylmethyl]-2-methyl-benzamide 2,3-Dichloro-N-(1-pyridin-3-yl- 2200cyclopentylmethyl)-benzamide 2-Chloro-5-methyl-N-(1-pyridin-3-yl- 2900cyclopentylmethyl)-benzamide N-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4-1200 ylmethyl]-2-trifluoromethyl-benzamide 2-Methyl-N-(1-pyridin-3-yl-3600 cyclopentylmethyl)-benzamideN-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4- 4300ylmethyl]-2-fluoro-3-trifluoromethyl- benzamide3-Chloro-N-[4-(4-chloro-phenyl)-tetrahydro- 890pyran-4-ylmethyl]-2-fluoro-benzamideN-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4- 3000ylmethyl]-2,5-difluoro-benzamide 2-Chloro-N-[1-(4-methoxy-phenyl)- 190cyclopentylmethyl]-5-methyl-benzamide2,3-Dichloro-N-[1-(4-methoxy-phenyl)- 260 cyclopentylmethyl]-benzamideN-[1-(4-Methoxy-phenyl)-cyclopentylmethyl]- 1400 2-methyl-benzamideN-[1-(4-Methoxy-phenyl)-cyclopentylmethyl]- 600 2,3-dimethyl-benzamide2-Chloro-5-methyl-N-(1-methyl-4-phenyl- 2.4piperidin-4-ylmethyl)-benzamide2-Methyl-N-(1-methyl-4-phenyl-piperidin-4- 64 ylmethyl)-benzamideN-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4- 3600ylmethyl]-2,3,5-trifluoro-benzamideN-[4-(4-Chloro-phenyl)-1-methyl-piperidin-4- 60ylmethyl]-2-methyl-benzamide2,3-Dichloro-N-[4-methyl-2-(6-methyl-pyridin- 1 3-yl)-pentyl]-benzamide2,3-Dimethyl-N-[4-methyl-2-(6-methyl- 4.4pyridin-3-yl)-pentyl]-benzamide2-Methyl-N-[4-methyl-2-(6-methyl-pyridin-3- 29 yl)-pentyl]-benzamide2-Chloro-5-methyl-N-[4-(6-methyl-pyridin-3- 3400yl)-tetrahydro-pyran-4-ylmethyl]-benzamide5-Bromo-2-chloro-N-[4-(4-chloro-phenyl)- 130tetrahydro-pyran-4-ylmethyl]-benzamide2-Chloro-N-[4-(4-chloro-phenyl)-tetrahydro- 800pyran-4-ylmethyl]-benzamide 2,3-dichloro-N-[[4,4-difluoro-1-(6-fluoro-3-0.28 pyridyl)cyclohexyl]methyl]benzamide2,3-dichloro-N-[[4,4-difluoro-1-(6-fluoro-3- 0.28pyridyl)cyclohexyl]methyl]benzamide2-chloro-N-[[4,4-difluoro-1-(6-fluoro-3- 14pyridyl)cyclohexyl]methyl]-6-fluoro- benzamide2-chloro-N-[[4,4-difluoro-1-(6-fluoro-3- 0.76pyridyl)cyclohexyl]methyl]-5-methyl- benzamide2-chloro-N-[[4,4-difluoro-1-(6-fluoro-3- 1.2pyridyl)cyclohexyl]methyl]-5- (trifluoromethyl)benzamideN-((4,4-difluoro-1-(6-fluoropyridin-3- 190yl)cyclohexyl)methyl)-2-fluorobenzamideN-((4,4-difluoro-1-(6-fluoropyridin-3- 100yl)cyclohexyl)methyl)-2-fluoro-3- methoxybenzamide2-chloro-N-((4,4-difluoro-1-(6-fluoropyridin-3- 8.7yl)cyclohexyl)methyl)-5- (methylsulfonyl)benzamide2-chloro-N-((4,4-difluoro-1-(6-fluoropyridin-3- 25yl)cyclohexyl)methyl)benzamide N-((4,4-difluoro-1-(6-fluoropyridin-3- 65yl)cyclohexyl)methyl)-2-fluoro-5- methoxybenzamideN-((4,4-difluoro-1-(6-fluoropyridin-3- 78yl)cyclohexyl)methyl)-2-fluoro-3- methylbenzamideN-((4,4-difluoro-1-(6-fluoropyridin-3- 1500yl)cyclohexyl)methyl)-2,5-difluorobenzamide2,5-dichloro-N-((4,4-difluoro-1-(6- 2.3 fluoropyridin-3-yl)cyclohexyl)methyl)benzamide2-chloro-N-((4,4-difluoro-1-(6-fluoropyridin-3- 0.83yl)cyclohexyl)methyl)-5-methoxybenzamideN-((4,4-difluoro-1-(6-fluoropyridin-3- 290yl)cyclohexyl)methyl)-2,3-difluorobenzamide2,3-dichloro-N-((4-(4-chlorophenyl)tetrahydro- 432H-pyran-4-yl)methyl)benzamide 2,3-dichloro-N-((4-(4- 41(trifluoromethyl)phenyl)tetrahydro-2H-pyran- 4-yl)methyl)benzamide2,3-dichloro-N-((4,4-difluoro-1-(6- 1.2 (trifluoromethyl)pyridin-3-yl)cyclohexyl)methyl)benzamide2,3-dichloro-N-((4-(6-(trifluoromethyl)pyridin- 523-yl)tetrahydro-2H-pyran-4- yl)methyl)benzamide2,3-dichloro-N-((1-(6-cyclopropylpyridin-3- 1.3yl)-4,4-difluorocyclohexyl)methyl)benzamide2,3-dichloro-N-((4,4-difluoro-1-(6- 0.96 methoxypyridin-3-yl)cyclohexyl)methyl)benzamide 2-cyano-N-((4,4-difluoro-1-(6- 150(trifluoromethyl)pyridin-3- yl)cyclohexyl)methyl)benzamide2-chloro-N-((4,4-difluoro-1-(6- 1800 (trifluoromethyl)pyridin-3-yl)cyclohexyl)methyl)-4- (methylsulfonyl)benzamideN-((4,4-difluoro-1-(6-(trifluoromethyl)pyridin- 2.63-yl)cyclohexyl)methyl)-2-methylbenzamide2,3-dichloro-N-(2-cyclopropyl-2-(6- 120(trifluoromethyl)pyridin-3-yl)ethyl)benzamideN-((4,4-difluoro-1-(6-(trifluoromethyl)pyridin- 4803-yl)cyclohexyl)methyl)-2- (methylsulfonyl)benzamide2,3-dichloro-N-((4,4-difluoro-1-(5- 1.2 fluoropyridin-3-yl)cyclohexyl)methyl)benzamide 2,3-dichloro-N-[3-cyclopropyl-2-[6- 0.55(trifluoromethyl)-3-pyridyl]propyl]benzamide2-chloro-N-[3-cyclopropyl-2-[6- 3.4(trifluoromethyl)-3-pyridyl]propyl]benzamideN-((4,4-difluoro-1-(6-(trifluoromethyl)pyridin- 43-yl)cyclohexyl)methyl)-3-fluoro-2- methylbenzamideN-((4,4-difluoro-1-(6-(trifluoromethyl)pyridin- 1.63-yl)cyclohexyl)methyl)-3-methoxy-2- methylbenzamideN-((4,4-difluoro-1-(6-(trifluoromethyl)pyridin- 9.13-yl)cyclohexyl)methyl)-5-fluoro-2- methylbenzamideN-((4,4-difluoro-1-(6-(trifluoromethyl)pyridin- 393-yl)cyclohexyl)methyl)-2-methyl-5- (trifluoromethyl)benzamide3-bromo-N-((4,4-difluoro-1-(6- 0.71 (trifluoromethyl)pyridin-3-yl)cyclohexyl)methyl)-2-methylbenzamide 2-chloro-N-((4,4-difluoro-1-(6-0.54 (trifluoromethyl)pyridin-3- yl)cyclohexyl)methyl)-3-methylbenzamide3-cyano-N-((4,4-difluoro-1-(6- 45 (trifluoromethyl)pyridin-3-yl)cyclohexyl)methyl)-2-methylbenzamide2,3-dichloro-N-(2-(5-chloropyridin-3-yl)-3- 5.5cyclopropylpropyl)benzamide 2,3-dichloro-N-(2-(4-chlorophenyl)-2- 120phenylethyl)benzamide 2,3-dichloro-N-[3-cyclopropyl-2-(2,6- 1300dimethyl-3-pyridyl)propyl]benzamide2,3-dichloro-N-[2-(2-methylpyrimidin-5-yl)-3- 7.1 [1-(trifluoromethyl)cyclopropyl]propyl]benzamide(+)2-chloro-N-[3-cyclopropyl-2-[6- 63(trifluoromethyl)-3-pyridyl]propyl]benzamide(−)2-chloro-N-[3-cyclopropyl-2-[6- 2.3(trifluoromethyl)-3-pyridyl]propyl]benzamide(+)2,3-dichloro-N-[3-cyclopropyl-2-[6- 2.6(trifluoromethyl)-3-pyridyl]propyl]benzamide(−)2,3-dichloro-N-[3-cyclopropyl-2-[6- 0.31(trifluoromethyl)-3-pyridyl]propyl]benzamide 2,3-dichloro-N-[3-[1- 19(trifluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide2,3-dichloro-N-[2-(6-cyclopropyl-3-pyridyl)-3- 15 [1-(trifluoromethyl)cyclopropyl]propyl]benzamide2,3-dichloro-N-[2-(6-cyclopropyl-3-pyridyl)-3- 0.76 [1-(difluoromethyl)cyclopropyl]propyl]benzamide(+)2-chloro-N-[3-cyclopropyl-2-[6- 1100(trifluoromethyl)-3-pyridyl]propyl]-3- (trifluoromethyl)benzamide(−)2-chloro-N-[3-cyclopropyl-2-[6- 110(trifluoromethyl)-3-pyridyl]propyl]-3- (trifluoromethyl)benzamide2,3-dichloro-N-[3-[1- 1.6 (difluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide(−)2,3-dichloro-N-[2-(2-methylpyrimidin-5-yl)- 64 3-[1-(trifluoromethyl)cyclopropyl]propyl]benzamide(+)2,3-dichloro-N-[2-(2-methylpyrimidin-5- 1.5 yl)-3-[1-(trifluoromethyl)cyclopropyl]propyl]benzamide(−)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-3- 650 [1-(trifluoromethyl)cyclopropyl]propyl]benzamide(+)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-3- 130 [1-(trifluoromethyl)cyclopropyl]propyl]benzamide2-chloro-N-[2-(6-cyclopropyl-3-pyridyl)-3-[1- 94(trifluoromethyl)cyclopropyl]propyl]benzamideN-[2-(6-cyclopropyl-3-pyridyl)-3-[1- 1700(trifluoromethyl)cyclopropyl]propyl]-2-fluoro- benzamide2-chloro-N-[3-cyclopropyl-2-(2- 1200methylpyrimidin-5-yl)propyl]benzamide2,3-dichloro-N-[3-cyclopropyl-2-(2- 60methylpyrimidin-5-yl)propyl]benzamide 2-chloro-N-[3-[1- 2.1(trifluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide 2-fluoro-N-[3-[1- 430(trifluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide2-chloro-N-[[4,4-difluoro-1-(2- 120 methylpyrimidin-5-yl)cyclohexyl]methyl]benzamide 2,3-dichloro-N-[[4,4-difluoro-1-(2- 8.6methylpyrimidin-5- yl)cyclohexyl]methyl]benzamide2,3-dichloro-N-[3-cyclopropyl-2-[2- 0.88 (trifluoromethyl)pyrimidin-5-yl]propyl]benzamide 2,3-dichloro-N-[[4,4-difluoro-1-[6-(1-hydroxy- 231-methyl-ethyl)-3- pyridyl]cyclohexyl]methyl]benzamide2-chloro-N-[[4,4-difluoro-1-[6-(1-hydroxy-1- 380 methyl-ethyl)-3-pyridyl]cyclohexyl]methyl]benzamide (+)2-chloro-N-[3-cyclopropyl-2-[6-12 (trifluoromethyl)-3-pyridyl]propyl]-3-methoxy- benzamide(−)2-chloro-N-[3-cyclopropyl-2-[6- 4.2(trifluoromethyl)-3-pyridyl]propyl]-3-methoxy- benzamide(+)2-chloro-N-[3-cyclopropyl-2-[6- 50(trifluoromethyl)-3-pyridyl]propyl]-6-fluoro- benzamide(−)2-chloro-N-[3-cyclopropyl-2-[6- 2.1(trifluoromethyl)-3-pyridyl]propyl]-6-fluoro- benzamide(+)N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3- 990pyridyl]propyl]-2-methoxy-benzamide(−)N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3- 53pyridyl]propyl]-2-methoxy-benzamide(+)N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3- 740pyridyl]propyl]-2,6-difluoro-benzamide(−)N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3- 130pyridyl]propyl]-2,6-difluoro-benzamide(+)2-chloro-N-[3-cyclopropyl-2-[6- 560(trifluoromethyl)-3-pyridyl]propyl]-5- methylsulfonyl-benzamide(−)2-chloro-N-[3-cyclopropyl-2-[6- 8.1(trifluoromethyl)-3-pyridyl]propyl]-5- methylsulfonyl-benzamide2,3-dichloro-N-((4,4-difluoro-1-(4-methyl-1H- 90imidazol-1-yl)cyclohexyl)methyl)benzamide(+)2-chloro-N-[3-cyclopropyl-2-[6- 11(trifluoromethyl)-3-pyridyl]propyl]-3-fluoro- benzamide2(−)-chloro-N-[3-cyclopropyl-2-[6- 2.9(trifluoromethyl)-3-pyridyl]propyl]-3-fluoro- benzamide(−)2-chloro-N-[3-cyclopropyl-2-(6-fluoro-3- 16 pyridyl)propyl]benzamide(+)2-chloro-N-[3-cyclopropyl-2-(6-fluoro-3- 510 pyridyl)propyl]benzamideN-(1-(1-(6-bromopyridin-3-yl)-4,4- 43 difluorocyclohexyl)ethyl)-2,3-dichlorobenzamide (−)2,3-dichloro-N-[3-cyclopropyl-2-(2- 39methylpyrimidin-5-yl)propyl]benzamide(+)2,3-dichloro-N-[3-cyclopropyl-2-(2- 260methylpyrimidin-5-yl)propyl]benzamide 2-chloro-N-((4,4-difluoro-1-(6- 2(trifluoromethyl)pyridin-3- yl)cyclohexyl)methyl)benzamide2,3-dichloro-N-((4,4-difluoro-1-(6- 7.3 methylpyridin-3-yl)cyclohexyl)methyl)benzamide 2-chloro-N-((4,4-difluoro-1-(6- 7.1(trifluoromethyl)pyridin-3- yl)cyclohexyl)methyl)-3-methoxybenzamide2-chloro-N-((4,4-difluoro-1-(6- 1.4 (trifluoromethyl)pyridin-3-yl)cyclohexyl)methyl)-3-fluorobenzamide2-chloro-N-((4,4-difluoro-1-(6-fluoropyridin-3- 5.3yl)cyclohexyl)methyl)-3-fluorobenzamide 3-chloro-N-((4,4-difluoro-1-(6-3.2 (trifluoromethyl)pyridin-3- yl)cyclohexyl)methyl)-2-fluorobenzamide3-chloro-N-((4,4-difluoro-1-(6-fluoropyridin-3- 11yl)cyclohexyl)methyl)-2-fluorobenzamide 3-chloro-N-(3-cyclopropyl-2-(6-660 (trifluoromethyl)pyridin-3-yl)propyl)-2- fluorobenzamide2-chloro-N-(3-cyclopropyl-2-(6- 310(trifluoromethyl)pyridin-3-yl)propyl)-4- fluorobenzamide2,6-dichloro-N-(3-cyclopropyl-2-(6- 0.71 (trifluoromethyl)pyridin-3-yl)propyl)benzamide 2-chloro-N-[3-cyclopropyl-2-methyl-2-[2- 21(trifluoromethyl)pyrimidin-5- yl]propyl]benzamide2-chloro-N-[3-cyclopropyl-2-methyl-2-[2- 16(trifluoromethyl)pyrimidin-5-yl]propyl]-3- fluoro-benzamide(−)2,3-dichloro-N-[3-cyclopropyl-2-[2- 0.86(trifluoromethyl)pyrimidin-5- yl]propyl]benzamide(+)2,3-dichloro-N-[3-cyclopropyl-2-[2- 3.9 (trifluoromethyl)pyrimidin-5-yl]propyl]benzamide (+)2-chloro-N-[3-cyclopropyl-2-[2- 38(trifluoromethyl)pyrimidin-5- yl]propyl]benzamide(−)2-chloro-N-[3-cyclopropyl-2-[2- 3.2 (trifluoromethyl)pyrimidin-5-yl]propyl]benzamide (+)2-chloro-N-[3-cyclopropyl-2-[2- 50(trifluoromethyl)pyrimidin-5-yl]propyl]-3- fluoro-benzamide(−)2-chloro-N-[3-cyclopropyl-2-[2- 4.7(trifluoromethyl)pyrimidin-5-yl]propyl]-3- fluoro-benzamide(+)2-chloro-N-[3-cyclopropyl-2-[2- 41(trifluoromethyl)pyrimidin-5-yl]propyl]-6- fluoro-benzamide2,3-dichloro-N-[2-(4-chlorophenyl)-2- 1.6tetrahydropyran-4-yl-ethyl]benzamide 2-chloro-N-[2-(4-chlorophenyl)-2-14 tetrahydropyran-4-yl-ethyl]benzamide2-chloro-N-[2-(4-chlorophenyl)-2- 30tetrahydropyran-4-yl-ethyl]-6-fluoro- benzamide2-chloro-N-[2-(4-chlorophenyl)-2- 15tetrahydropyran-4-yl-ethyl]-3-fluoro- benzamide2,6-dichloro-N-(3-cyclopropyl-2-(2- 5.1 (trifluoromethyl)pyrimidin-5-yl)propyl)benzamide 2-chloro-N-(3-cyclopropyl-2-(2- 13(trifluoromethyl)pyrimidin-5- yl)propyl)benzamide2-chloro-N-(3-cyclopropyl-2-(2- 14(trifluoromethyl)pyrimidin-5-yl)propyl)-3- fluorobenzamide2-chloro-N-(3-cyclopropyl-2-(2- 22(trifluoromethyl)pyrimidin-5-yl)propyl)-6- fluorobenzamide2,3-dichloro-N-[[4-[2- 250 (trifluoromethyl)pyrimidin-5-yl]tetrahydropyran-4-yl]methyl]benzamide2-chloro-N-[[4-[2-(trifluoromethyl)pyrimidin- 44005-yl]tetrahydropyran-4-yl]methyl]benzamide 2-chloro-6-fluoro-N-[[4-[2-1600 (trifluoromethyl)pyrimidin-5-yl]tetrahydropyran-4-yl]methyl]benzamide(−)2-chloro-N-[3-cyclopropyl-2-[2- 3.4(trifluoromethyl)pyrimidin-5-yl]propyl]-3- methoxy-benzamide(+)2-chloro-N-[3-cyclopropyl-2-[2- 14(trifluoromethyl)pyrimidin-5-yl]propyl]-3- methoxy-benzamide(−)N-[3-cyclopropyl-2-[2- 1.4 (trifluoromethyl)pyrimidin-5-yl]propyl]-3-methoxy-2-methyl-benzamide (+)N-[3-cyclopropyl-2-[2- 9(trifluoromethyl)pyrimidin-5-yl]propyl]-3- methoxy-2-methyl-benzamide2,3-dichloro-N-[3-(1-fluorocyclopropyl)-2-[6- 3.7(trifluoromethyl)-3-pyridyl]propyl]benzamide(−)2,6-dichloro-N-[3-cyclopropyl-2-[6- 1.2(trifluoromethyl)-3-pyridyl]propyl]benzamide(+)2,6-dichloro-N-[3-cyclopropyl-2-[6- 0.89(trifluoromethyl)-3-pyridyl]propyl]benzamide(−)2,6-dichloro-N-[3-cyclopropyl-2-[2- 0.82(trifluoromethyl)pyrimidin-5- yl]propyl]benzamide(+)2,6-dichloro-N-[3-cyclopropyl-2-[2- 3.8 (trifluoromethyl)pyrimidin-5-yl]propyl]benzamide 2,3-dichloro-N-[3-(1-fluorocyclopropyl)-2-[2- 9.3(trifluoromethyl)pyrimidin-5- yl]propyl]benzamide2,3-dichloro-N-[2-(2-methylpyrimidin-5-yl)-2- 50(4-pyridyl)ethyl]benzamide 2-chloro-N-[2-(2-methylpyrimidin-5-yl)-2-(4-1300 pyridyl)ethyl]benzamide2-chloro-6-fluoro-N-[2-(2-methylpyrimidin-5- 640yl)-2-(4-pyridyl)ethyl]benzamide2-chloro-3-fluoro-N-[2-(2-methylpyrimidin-5- 860yl)-2-(4-pyridyl)ethyl]benzamide (−)2,6-dichloro-N-[3-cyclopropyl-2-(2-9.9 methylpyrimidin-5-yl)propyl]benzamide(+)2,6-dichloro-N-[3-cyclopropyl-2-(2- 220methylpyrimidin-5-yl)propyl]benzamide(+)2-chloro-N-[3-cyclopropyl-2-methyl-2-[2- 460(trifluoromethyl)pyrimidin-5- yl]propyl]benzamide(−)2-chloro-N-[3-cyclopropyl-2-methyl-2-[2- 17(trifluoromethyl)pyrimidin-5- yl]propyl]benzamide2,3-dichloro-N-[[4,4-difluoro-1-[2- 0.95 (trifluoromethyl)pyrimidin-5-yl]cyclohexyl]methyl]benzamide(+)2-chloro-N-[3-cyclopropyl-2-methyl-2-[2- 360(trifluoromethyl)pyrimidin-5-yl]propyl]-3- fluoro-benzamide(−)2-chloro-N-[3-cyclopropyl-2-methyl-2-[2- 34(trifluoromethyl)pyrimidin-5-yl]propyl]-3- fluoro-benzamide(+)2,3-dichloro-N-[3-cyclopropyl-2-methyl-2- 74[2-(trifluoromethyl)pyrimidin-5- yl]propyl]benzamide(−)2,3-dichloro-N-[2-(2-methylpyrimidin-5-yl)- 582-tetrahydropyran-4-yl-ethyl]benzamide(+)2,3-dichloro-N-[2-(2-methylpyrimidin-5- 28yl)-2-tetrahydropyran-4-yl-ethyl]benzamide(−)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-2- 570tetrahydropyran-4-yl-ethyl]benzamide(+)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-2- 970tetrahydropyran-4-yl-ethyl]benzamide2,3-dichloro-N-[2-(4,4-difluorocyclohexyl)-2- 6.2(2-methylpyrimidin-5-yl)ethyl]benzamide2-chloro-N-[2-(4,4-difluorocyclohexyl)-2-(2- 90methylpyrimidin-5-yl)ethyl]benzamide (+)2-chloro-N-[3-[1- 2.4(trifluoromethyl)cyclopropyl]-2-[2- (trifluoromethyl)pyrimidin-5-yl]propyl]benzamide 2-chloro-6-fluoro-N-[2-(2-methylpyrimidin-5- 1900yl)-2-tetrahydropyran-4-yl-ethyl]benzamide2-chloro-3-fluoro-N-[2-(2-methylpyrimidin-5- 210yl)-2-tetrahydropyran-4-yl-ethyl]benzamide2-chloro-N-[2-(4,4-difluorocyclohexyl)-2-(2- 150methylpyrimidin-5-yl)ethyl]-6-fluoro- benzamide2-chloro-N-[2-(4,4-difluorocyclohexyl)-2-(2- 83methylpyrimidin-5-yl)ethyl]-3-fluoro- benzamide (+)2-chloro-N-[3-[1-0.09 (trifluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide (−)2-chloro-N-[3-[1- 32(trifluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide (+)2,3-dichloro-N-[3-[1- 12(trifluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide (−)2,3-dichloro-N-[3-[1- 25(trifluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide(+)2-chloro-3-fluoro-N-[3-[1- 4.5 (trifluoromethyl)cyclopropyl]-2-[2-(trifluoromethyl)pyrimidin-5- yl]propyl]benzamide(−)2-chloro-3-fluoro-N-[3-[1- 29 (trifluoromethyl)cyclopropyl]-2-[2-(trifluoromethyl)pyrimidin-5- yl]propyl]benzamide(+)2,3-dichloro-N-[3-[1- 1.6 (trifluoromethyl)cyclopropyl]-2-[2-(trifluoromethyl)pyrimidin-5- yl]propyl]benzamide(−)2,3-dichloro-N-[3-[1- 21 (trifluoromethyl)cyclopropyl]-2-[2-(trifluoromethyl)pyrimidin-5- yl]propyl]benzamide(+)2-chloro-3-fluoro-N-[3-[1- 7.2 (trifluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide(−)2-chloro-3-fluoro-N-[3-[1- 16 (trifluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide(+)2,3-dichloro-N-[3-cyclopropyl-2-[6-(1- 740 hydroxy-1-methyl-ethyl)-3-pyridyl]propyl]benzamide (−)2,3-dichloro-N-[3-cyclopropyl-2-[6-(1- 30hydroxy-1-methyl-ethyl)-3- pyridyl]propyl]benzamide(+)2,3-dichloro-N-[2-tetrahydropyran-4-yl-2- 4.1[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2,3-dichloro-N-[2-tetrahydropyran-4-yl-2-[2- 11(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(+)2-chloro-N-[2-tetrahydropyran-4-yl-2-[2- 51(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2-chloro-N-[2-tetrahydropyran-4-yl-2-[2- 56(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(+)2-chloro-6-fluoro-N-[2-tetrahydropyran-4- 56yl-2-[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2-chloro-6-fluoro-N-[2-tetrahydropyran-4- 68yl-2-[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(+)2-chloro-3-fluoro-N-[2-tetrahydropyran-4- 32yl-2-[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2-chloro-3-fluoro-N-[2-tetrahydropyran-4- 64yl-2-[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(+)2,6-dichloro-N-[2-phenyl-2-[6- 12(trifluoromethyl)-3-pyridyl]ethyl]benzamide(−)2,6-dichloro-N-[2-phenyl-2-[6- 18(trifluoromethyl)-3-pyridyl]ethyl]benzamide2,4-dichloro-N-(2-phenyl-2-(6- 25(trifluoromethyl)pyridin-3-yl)ethyl)benzamide2-chloro-6-fluoro-N-[1-[4-(2-methylpyrimidin- 555-yl)tetrahydropyran-4-yl]ethyl]benzamide2-chloro-3-fluoro-N-[1-[4-(2-methylpyrimidin- 155-yl)tetrahydropyran-4-yl]ethyl]benzamide2,3-dichloro-N-((3-(2-methylpyrimidin-5- 15yl)tetrahydrofuran-3-yl)methyl)benzamide(+)2,3-dichloro-N-[2-(4-fluorophenyl)-2-[6- 12(trifluoromethyl)-3-pyridyl]ethyl]benzamide(−)2,3-dichloro-N-[2-(4-fluorophenyl)-2-[6- 9.4(trifluoromethyl)-3-pyridyl]ethyl]benzamide(+)2-chloro-6-fluoro-N-[2-(4-fluorophenyl)-2- 15[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide(−)2-chloro-6-fluoro-N-[2-(4-fluorophenyl)-2- 8.5[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide(+)2-chloro-3-fluoro-N-[2-(4-fluorophenyl)-2- 4.6[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide(−)2-chloro-3-fluoro-N-[2-(4-fluorophenyl)-2- 7[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide(+)2-chloro-N-[2-(4-fluorophenyl)-2-[6- 2.2(trifluoromethyl)-3-pyridyl]ethyl]benzamide(−)2-chloro-N-[2-(4-fluorophenyl)-2-[6- 3.1(trifluoromethyl)-3-pyridyl]ethyl]benzamide2-chloro-N-[2-(4-pyridyl)-2-[2- 30 (trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide 2,3-dichloro-N-[2-(4-pyridyl)-2-[2- 6.2(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide2-chloro-N-[2-(4-pyridyl)-2-[6- 11(trifluoromethyl)-3-pyridyl]ethyl]benzamide2,3-dichloro-N-[2-(4-pyridyl)-2-[6- 200(trifluoromethyl)-3-pyridyl]ethyl]benzamide(+)2,3-dichloro-N-[2-(4-fluorophenyl)-2-[2- 1.1(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2,3-dichloro-N-[2-(4-fluorophenyl)-2-[2- 1.2(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(+)2-chloro-N-[2-(4-fluorophenyl)-2-[2- 4.4(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2-chloro-N-[2-(4-fluorophenyl)-2-[2- 2 (trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide 2,3-dichloro-N-[1-[4,4-difluoro-1-(2- 960methylpyrimidin-5- yl)cyclohexyl]ethyl]benzamide2-chloro-N-[1-[4,4-difluoro-1-(2- 1600 methylpyrimidin-5-yl)cyclohexyl]ethyl]benzamide(+)2-chloro-6-fluoro-N-[2-(4-fluorophenyl)-2- 6.7[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2-chloro-6-fluoro-N-[2-(4-fluorophenyl)-2- 2.6[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(+)2-chloro-3-fluoro-N-[2-(4-fluorophenyl)-2- 4.8[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2-chloro-3-fluoro-N-[2-(4-fluorophenyl)-2- 1.8[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide2-chloro-N-[1-[4,4-difluoro-1-(2- 1400methylpyrimidin-5-yl)cyclohexyl]ethyl]-6- fluoro-benzamide2-chloro-N-[1-[4,4-difluoro-1-(2- 2000methylpyrimidin-5-yl)cyclohexyl]ethyl]-3- fluoro-benzamide(−)2,3-dichloro-N-[2-(4,4-difluorocyclohexyl)- 162-(2-methylpyrimidin-5-yl)ethyl]benzamide(+)2,3-dichloro-N-[2-(4,4-difluorocyclohexyl)- 8.42-(2-methylpyrimidin-5-yl)ethyl]benzamide(+)2-chloro-N-[2-(4,4-difluorocyclohexyl)-2- 45[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3- fluoro-benzamide(−)2-chloro-N-[2-(4,4-difluorocyclohexyl)-2-[2- 44(trifluoromethyl)pyrimidin-5-yl]ethyl]-3- fluoro-benzamide(+)2-chloro-N-[2-(4,4-difluorocyclohexyl)-2- 32[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2-chloro-N-[2-(4,4-difluorocyclohexyl)-2-[2- 6.4(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(+)2,3-dichloro-N-[2-(4,4-difluorocyclohexyl)- 5.72-[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(−)2,3-dichloro-N-[2-(4,4-difluorocyclohexyl)- 4.32-[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide(+)2-chloro-N-[2-(4,4-difluorocyclohexyl)-2- 75[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-6- fluoro-benzamide(−)2-chloro-N-[2-(4,4-difluorocyclohexyl)-2-[2- 61(trifluoromethyl)pyrimidin-5-yl]ethyl]-6- fluoro-benzamide2,3-dichloro-N-[4-methoxy-2-[2- 2200 (trifluoromethyl)pyrimidin-5-yl]butyl]benzamide 2,3-dichloro-N-(2-phenyl-2-pyridazin-4-yl- 94ethyl)benzamide 2,4-dichloro-N-(2-phenyl-2-pyridazin-4-yl- 720ethyl)benzamide (+)2,3-dichloro-N-[3-cyclopropyl-2-[2- 23(difluoromethyl)pyrimidin-5- yl]propyl]benzamide(−)2,3-dichloro-N-[3-cyclopropyl-2-[2- 1.9 (difluoromethyl)pyrimidin-5-yl]propyl]benzamide (+)2-chloro-N-[3-cyclopropyl-2-[6- 640(difluoromethyl)-3-pyridyl]propyl]benzamide(−)2-chloro-N-[3-cyclopropyl-2-[6- 17(difluoromethyl)-3-pyridyl]propyl]benzamide(+)2,3-dichloro-N-[3-cyclopropyl-2-[6- 24(difluoromethyl)-3-pyridyl]propyl]benzamide(−)2,3-dichloro-N-[3-cyclopropyl-2-[6- 1.9(difluoromethyl)-3-pyridyl]propyl]benzamide(+)2-chloro-N-[3-cyclopropyl-2-[6- 800(difluoromethyl)-3-pyridyl]propyl]-3-fluoro- benzamide(−)2-chloro-N-[3-cyclopropyl-2-[6- 19(difluoromethyl)-3-pyridyl]propyl]-3-fluoro- benzamide(+)2-chloro-N-[3-cyclopropyl-2-[6- 4.4(difluoromethyl)-3-pyridyl]propyl]-3-methoxy- benzamideN-[4,4-Difluoro-1-(6-fluoro-pyridin-3-yl)- 14cyclohexylmethyl]-2-fluoro-benzamide

What is claimed:
 1. A method of treating pain comprising administering atherapeutically effective amount of at least one compound of formula I

wherein R¹ is pyridyl, pyrazinyl, pyridazinyl, or pyrimidyl, each ofwhich is optionally substituted with one or more C₁₋₆alkyl, halogen,hydroxy, C₁₋₆hydroxyalkyl, C₁₋₄fluoroalkyl, C₃₋₆cycloalkyl,C₁₋₄fluoroalkoxy, cyano or —SO₂R⁸; wherein R² is C₃₋₆cycloalkyl,C₃₋₆cyclohetalkyl, C₁₋₄fluoroalkyl, C₁₋₄fluoroalkoxy, C₁₋₄alkoxy,C₁₋₆alkenyl, C₁₋₆alkynyl, 6 membered heteroaryl, phenyl or C₁₋₄alkyloptionally substituted with one or more R⁹; wherein R³ is hydrogen,fluorine, C₁₋₄alkyl or C₁₋₄fluoroalkyl; or wherein R² and R³ combinewith the carbon to which they are attached to form cyclohexyl,tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl,pyrrolo, imidazo, azetidinyl, homomorpholinyl, homopiperidinyl orhomopiperazinyl each of which is optionally substituted with one or moreC₁₋₆alkyl, C₁₋₆alkenyl, C₃₋₆-cycloalkyl, C₁₋₆alkoxy, oxo, —NR⁶R⁷ orfluorine; wherein R⁴ is halogen, C₁₋₄fluoroalkyl, cyano, cyclopropyl,C₁₋₄alkyloxy, C₁₋₄fluoroalkyloxy, —SO₂R⁸, —NR⁶R⁷ or C₁₋₆alkyl; whereinR⁵ is halogen, C₁₋₆alkyl, C₁₋₄fluoroalkyl, cyano, —SO₂R⁸, —NR⁶R⁷,C₁₋₆alkoxy, C₁₋₄fluoroalkoxy or C₃₋₆-cycloalkyl; wherein R⁶ and R⁷independently of each other are hydrogen or C₁₋₆alkyl; wherein R⁸ isC₁₋₆alkyl, C₃₋₆cycloalkyl or C₁₋₄fluoroalkyl; wherein R⁹ is C₁₋₆alkyl,C₃₋₆cycloalkyl, —NR¹⁰R¹¹, C₁₋₄fluoroalkyl or 3 to 7 memberedheterocyclyl which is optionally substituted with one or more C₁₋₆alkyl,halogen, hydroxy, C₁₋₄fluoroalkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,C₁₋₄fluoroalkoxy or cyano; wherein R¹⁰ and R¹¹ independently of eachother are hydrogen or C₁₋₆alkyl; or wherein R¹⁰ and R¹¹ combine with thenitrogen to which they are attached to form piperazinyl, piperidinyl,morpholinyl, pyrrolidinyl, azetidinyl, homomorpholinyl, homopiperidinylor homopiperazinyl each of which is optionally substituted with one ormore C₁₋₆alkyl, C₁₋₆alkoxy, oxo or fluorine; and wherein n is 0-3; or apharmaceutically acceptable salt thereof; to a subject in need thereof.2. The method of claim 1 wherein the pain is acute pain.
 3. The methodof claim 1 wherein the pain is chronic pain.
 4. The method of claim 1wherein the pain is inflammatory pain.
 5. The method of claim 1 whereinthe pain is caused by morphine tolerance, fibromyalgia, neuralgia,osteoarthritis, rheumatoid arthritis, psoriatic arthritis, irritablebowel syndrome or inflammatory bowel disease, or is headache,neuropathic pain or post-operative pain.
 6. The method of claim 5wherein the pain is neuropathic pain.
 7. The method of claim 1, whereinthe compound is(−)2-chloro-N-[3-cyclopropyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide.8. The method of claim 1, wherein the compound is(−)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-6-fluorobenzamide.9. The method of claim 1, wherein the compound is(−)2,3-dichloro-N-[3-cyclopropyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide.10. The method of claim 1, wherein the compoundis(−)2,6-dichloro-N-[3-cyclopropyl-2[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide.11. The method of claim 1, wherein the compound is(+)2-chloro-N-[3-cyclopropyl-2[2-(trifluoromethyl)pyrimidin-5-yl]propyl]-3-fluoro-benzamide.12. The method of claim 1, wherein the compound is(+)-2-chloro-N-(3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide.13. The method of claim 1, wherein the compound is(+)2-chloro-N-[3-[1-(trifluoromethyl)cyclopropyl]-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide.14. The method of claim 1, wherein the compound is(+)-2,3-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propyl)benzamide.15. The method of claim 1, wherein the compound is(−)2,3-dichloro-N-[3-cyclopropyl-2-[2-(difluoromethyl)pyrimidin-5-yl]propyl]benzamide.16. The method of claim 1, wherein the compound is(+)2,3-dichloro-N-[3-[1-(trifluoromethyl)cyclopropyl]-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide.17. The method of claim 1, wherein the compound is(−)-2,6-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide.18. The method of claim 1, wherein the compound is(−)2-chloro-N-[3-cyclopropyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]-3-fluoro-benzamide.19. The method of claim 1, wherein the compound is(−)-2,3-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propyl)benzamide.20. The method of claim 1, wherein the compound is(−)2,3-dichloro-N-[3-[1-(trifluoromethyl)cyclopropyl]-2[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide.21. The method of claim 1, wherein the compound is(−)-2,3-dichloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide.22. The method of claim 1, wherein the compound is(+)2-chloro-3-fluoro-N-[3-[1-(trifluoromethyl)cyclopropyl]-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide.23. The method of claim 1, wherein the compound is(−)2,6-dichloro-N-[3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl]benzamide.